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Aspergillus vadensis CBS 113365, a close relative of A. niger , has been suggested as a more favourable alternative for recombinant protein production as it does not acidify the culture medium and produces very low levels of extracellular proteases. The aim of this study was to investigate the underlying cause of the non-amylolytic and non-proteolytic phenotype of A. vadensis CBS 113365. Our results demonstrate that the non-functionality of the amylolytic transcription factor AmyR in A. vadensis CBS 113365 is primarily attributed to the lack of functionality of its gene's promoter sequence. In contrast, a different mechanism is likely causing the lack of PrtT activity, which is the main transcriptional regulator of protease production. The findings presented here not only expand our understanding of the genetic basis behind the distinct characteristics of A. vadensis CBS 113365, but also underscore its potential as a favourable alternative for recombinant protein production. • Restoration of amylolytic activity of A. vadensis by introduction of A. niger amyR. • Promoter non-functionality of amyR causes low amylase activities in A. vadensis. • The prtT promoter has non-functional significance in A. vadensis. [ABSTRACT FROM AUTHOR]

Genome compartments are shaped by epigenetic marks and nuclear structure tethering. The most dramatic compartment changes occur during cell differentiation or cancer progression, but minor compartment changes in response to stimuli can have important biological consequences. Compartmentalization is generally robust and reinforced by many factors. Some genomic regions exist in states that make them more prone to compartment shift. Gene expression, replication timing, DNA damage, and the physical properties of the nucleus can both influence and be affected by genome spatial compartmentalization. The spatial segregation of the genome into compartments is a major feature of 3D genome organization. New data on mammalian chromosome organization across different conditions reveal important information about how and why these compartments form and change. A combination of epigenetic state, nuclear body tethering, physical forces, gene expression, and replication timing (RT) can all influence the establishment and alteration of chromosome compartments. We review the causes and implications of genomic regions undergoing a 'compartment switch' that changes their physical associations and spatial location in the nucleus. About 20–30% of genomic regions change compartment during cell differentiation or cancer progression, whereas alterations in response to a stimulus within a cell type are usually much more limited. However, even a change in 1–2% of genomic bins may have biologically relevant implications. Finally, we review the effects of compartment changes on gene regulation, DNA damage repair, replication, and the physical state of the cell. [ABSTRACT FROM AUTHOR]

Small non-coding RNAs (sRNAs) are about 50–500 nucleotides in length, regulate the gene expression at both transcriptional and posttranslational levels, and are critical players in microbial adaptation to different environmental conditions. Our current understanding of molecular processes underlying adaptation to harsh environments, including cold environments, is far from being complete. To understand the regulation of gene expression in psychrophilic bacteria and the roles of sRNAs in cold adaptation, we scanned the genome of psychrophilic and halotolerant bacterium Psychrobacter aquaticus using a comparative genomics-based approach. In total, 111 putative cis -regulatory RNAs (cis -sRNAs) exhibiting thermodynamic stability of their secondary structure were predicted, 43 of which were predicted to be able to bind to their respective targets and studied further. Six of the 43 cis -sRNAs, including cis2, cis9, cis19, cis28, cis32, and cis40, were predicted as regulators of regulatory proteins, revealing that regulatory proteins themselves are regulated by sRNAs. A major class of cis -sRNAs are considered regulators of the genes related to synthesizing and transporting amino acids, nucleotides, and other metabolites in Psychrobacter aquaticus. Several cis -sRNAs were identified to putatively function in modulating the expression of genes related to stress responses. Particularly, cis38 was identified as a regulator of the rhlB gene crucial for bacterial adaptation to cold environments and, therefore, was regarded as a cold regulator. A putative cis -sRNA homologous to cis38 was also found in Psychrobacter alimentarius , a psychrophilic bacterium isolated from Antarctica and Korean fermented food. Both cis8 and its homolog shared a conserved domain interacting with their respective targets, mRNAs of the rhlB genes. Understanding the mechanisms of cold regulators will provide future opportunities to engineer bacterial species encoding cold-adapted enzymes for industrial applications. [Display omitted] • sRNAs play important role in microbial adaptation by modulating the gene expression. • Genome-wide identification of sRNAs in Psychrobacter aquaticus was performed. • In total, 111 putative cis -RNAs were predicted, targets for 43 of these were predicted. • Six of the 43 cis -sRNAs were found as regulators of regulatory proteins. • sRNA cis38 having role in cold adaption was identified and regarded as a cold regulator. [ABSTRACT FROM AUTHOR]

Targeted novel treatment approaches for GBM using 4-amino cyanine and miRNA inhibitors. [Display omitted] • Developing novel therapeutic strategies is a promising approach for GBM. • ncRNAs play important roles in GBM pathogenesis, proliferation, and metastasis. • This review highlights the roles of miRNAs in GBM pathogenesis. • GBM treatment by combining 4-amino cyanine, and miRNAs-related Inhibitors. • Highlights the key challenges in miRNA therapy that need to be overcome. Glioblastoma (GBM) poses a formidable challenge in oncology due to its aggressive nature and dismal prognosis, with average survival rates around 15 months despite conventional treatments. This review proposes a novel therapeutic strategy for GBM by integrating microRNA (miRNA) therapy with 4-amino cyanine molecules possessing near-infrared (NIR) properties. miRNA holds promise in regulating gene expression, particularly in GBM, making it an attractive therapeutic target. 4-amino cyanine molecules, especially those with NIR properties, have shown efficacy in targeted tumor cell degradation. The combined approach addresses gene expression regulation and precise tumor cell degradation, offering a breakthrough in GBM treatment. Additionally, the review explores noncoding RNAs classification and characteristics, highlighting their role in GBM pathogenesis. Advanced technologies such as antisense oligonucleotides (ASOs), locked nucleic acids (LNAs), and peptide nucleic acids (PNAs) show potential in targeting noncoding RNAs therapeutically, paving the way for precision medicine in GBM. This synergistic combination presents an innovative approach with the potential to advance cancer therapy in the challenging landscape of GBM. [ABSTRACT FROM AUTHOR]

Mixed lineage leukemia–fusion proteins (MLL-FPs) are believed to maintain gene activation and induce MLL through aberrantly stimulating transcriptional elongation, but the underlying mechanisms are incompletely understood. Here, we show that both MLL1 and AF9, one of the major fusion partners of MLL1, mainly occupy promoters and distal intergenic regions, exhibiting chromatin occupancy patterns resembling that of RNA polymerase II in HEL, a human erythroleukemia cell line without MLL1 rearrangement. MLL1 and AF9 only coregulate over a dozen genes despite of their co-occupancy on thousands of genes. They do not interact with each other, and their chromatin occupancy is also independent of each other. Moreover, AF9 deficiency in HEL cells decreases global TBP occupancy while decreases CDK9 occupancy on a small number of genes, suggesting an accessory role of AF9 in CDK9 recruitment and a possible major role in transcriptional initiation via initiation factor recruitment. Importantly, MLL1 and MLL-AF9 occupy promoters and distal intergenic regions, exhibiting identical chromatin occupancy patterns in MLL cells, and MLL-AF9 deficiency decreased occupancy of TBP and TFIIE on major target genes of MLL-AF9 in iMA9, a murine acute myeloid leukemia cell line inducibly expressing MLL-AF9, suggesting that it can also regulate initiation. These results suggest that there is no difference between MLL1 and MLL-AF9 with respect to location and size of occupancy sites, contrary to what people have believed, and that MLL-AF9 may also regulate transcriptional initiation in addition to widely believed elongation. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a common condition associated with significant morbidity, mortality, and cost. Injured kidney tissue can regenerate after many forms of AKI. However, there are no treatments in routine clinical practice to encourage recovery. In part, this shortcoming is due to an incomplete understanding of the genetic mechanisms that orchestrate kidney recovery. The advent of high-throughput sequencing technologies and genetic mouse models has opened an unprecedented window into the transcriptional dynamics that accompany both successful and maladaptive repair. AKI recovery shares similar cell-state transformations with kidney development, which can suggest common mechanisms of gene regulation. Several powerful bioinformatic strategies have been developed to infer the activity of gene regulatory networks by combining multiple forms of sequencing data at single-cell resolution. These studies highlight not only shared stress responses but also key changes in gene regulatory networks controlling metabolism. Furthermore, chromatin immunoprecipitation studies in injured kidneys have revealed dynamic epigenetic modifications at enhancer elements near target genes. This review will highlight how these studies have enhanced our understanding of gene regulation in injury response and regeneration. [ABSTRACT FROM AUTHOR]

The long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) is involved in a variety of human cancers. Two overlapping NEAT1 isoforms, NEAT1_1 and NEAT1_2, are produced through mutually exclusive alternative 30 end formation. Previous studies extensively investigated NEAT1 dysregulation in tumors, but often failed to achieve distinct quantification of the two NEAT1 isoforms. Moreover, molecular mechanisms governing the biogenesis of NEAT1 isoforms and the functional impacts of their dysregulation in tumorigenesis remain poorly understood. In this study, we employed an isoform-specific quantification assay and found differential dysregulation of NEAT1 isoforms in patient-derived glioblastoma multiforme cells. We further showed usage of the NEAT1 proximal polyadenylation site (PAS) is a critical mechanism that controls glioma NEAT1 isoform production. CRISPRCas9–mediated PAS deletion reduced NEAT1_1 and reciprocally increased NEAT1_2, which enhanced nuclear paraspeckle formation in human glioma cells. Moreover, the utilization of the NEAT1 PAS is facilitated by the RNA-binding protein quaking (QKI), which binds to the proximal QKI recognition elements. Functionally, we identified transcriptomic changes and altered biological pathways caused by NEAT1 isoform imbalance in glioma cells, including the pathway for the regulation of cell migration. Finally, we demonstrated the forced increase of NEAT1_2 upon NEAT1 PAS deletion is responsible for driving glioma cell migration and promoting the expression of genes implicated in the regulation of cell migration. Together, our studies uncovered a novel mechanism that regulates NEAT1 isoforms and their functional impacts on the glioma transcriptome, which affects pathological pathways of glioma, represented by migration. [ABSTRACT FROM AUTHOR]

Accumulative evidence indicates a critical role of mitochondrial function in autism spectrum disorders (ASD), implying that ASD risk may be linked to mitochondrial dysfunction due to DNA (mtDNA) variations. Although a few studies have explored the association between mtDNA variations and ASD, the role of mtDNA in ASD is still unclear. Here, we aimed to investigate whether mitochondrial DNA haplogroups are associated with the risk of ASD. Two European cohorts and an Ashkenazi Jewish (AJ) cohort were analyzed, including 2,062 ASD patients in comparison with 4,632 healthy controls. DNA samples were genotyped using Illumina HumanHap550/610 and Illumina 1M arrays, inclusive of mitochondrial markers. Mitochondrial DNA (mtDNA) haplogroups were identified from genotyping data using HaploGrep2. A mitochondrial genome imputation pipeline was established to detect mtDNA variants. We conducted a case-control study to investigate potential associations of mtDNA haplogroups and variants with the susceptibility to ASD. We observed that the ancient adaptive mtDNA haplogroup K was significantly associated with decreased risk of ASD by the investigation of 2 European cohorts including a total of 2,006 cases and 4,435 controls (odds ratio = 0.64, P= 1.79 × 10–5), and we replicated this association in an Ashkenazi Jewish (AJ) cohort including 56 cases and 197 controls (odds ratio = 0.35, P = 9.46 × 10–3). Moreover, we demonstrate that the mtDNA variants rs28358571, rs28358584, and rs28358280 are significantly associated with ASD risk. Further expression quantitative trait loci (eQTLs) analysis indicated that the rs28358584 and rs28358280 genotypes are associated with expression levels of nearby genes in brain tissues, suggesting those mtDNA variants may confer risk for ASD via regulation of expression levels of genes encoded by the mitochondrial genome. This study helps to shed light on the contribution of mitochondria in ASD and provides new insights into the genetic mechanism underlying ASD, suggesting the potential involvement of mtDNA-encoded proteins in the development of ASD. Increasing evidence indicates that mitochondrial dysfunction may be linked to autism spectrum disorder (ASD). This study investigated potential associations of mitochondrial DNA (mtDNA) variants in 2 European and Ashkenazi Jewish cohorts including 2,062 individuals with ASD and 4,632 healthy controls. Researchers found that the ancient mtDNA haplogroup K was linked to a reduced risk of ASD in both European and Ashkenazi Jewish populations. Additionally, specific mtDNA variants were associated with ASD risk and were shown to influence the expression of nearby genes in the brain. These findings highlight the potential involvement of mtDNA in ASD development, offering new insights into the genetic mechanisms underlying the disorder. [ABSTRACT FROM AUTHOR]

Clustered regularly interspaced short palindromic repeats (CRISPR) activation (CRISPRa) technology allows pooled or targeted upregulation of gene expression. This new technical capacity helps to identify genes that, when upregulated, modify cell physiology and/or disease progression. Various CRISPR activation strategies have been described, with single and combinatorial activator domains enhancing gene activation efficiency. Different activation domains are suited to specific genes and cell types. CRISPRa pooled screening has enabled diverse applications in drug discovery, providing new insight into cell responses and cell differentiation, and even an understanding of SARS-CoV-2 mechanisms during infection. CRISPRa also demonstrates strong potential for in vivo applications for various diseases and conditions. Clustered regularly interspaced short palindromic repeats (CRISPR) activation (CRISPRa) has become an integral part of the molecular biology toolkit. CRISPRa genetic screens are an exciting high-throughput means of identifying genes the upregulation of which is sufficient to elicit a given phenotype. Activation machinery is continually under development to achieve greater, more robust, and more consistent activation. In this review, we offer a succinct technological overview of available CRISPRa architectures and a comprehensive summary of pooled CRISPRa screens. Furthermore, we discuss contemporary applications of CRISPRa across broad fields of research, with the aim of presenting a view of exciting emerging applications for CRISPRa screening. Clustered regularly interspaced short palindromic repeats (CRISPR) activation (CRISPRa) has become an integral part of the molecular biology toolkit. CRISPRa genetic screens are an exciting high-throughput means of identifying genes the upregulation of which is sufficient to elicit a given phenotype. Activation machinery to achieve greater, more robust, and more consistent activation is continually under development. In this review, we offer a succinct technological overview of available CRISPRa architectures and a comprehensive summary of pooled CRISPRa screens. Furthermore, we discuss contemporary applications of CRISPRa across broad fields of research, with the aim of presenting a view of exciting emerging applications for CRISPRa screening. [ABSTRACT FROM AUTHOR]

Liquid-liquid phase separation (LLPS) describes many biochemical processes, including hydrogel formation, in the integrity of macromolecular assemblages and existence of membraneless organelles, including ribosome, nucleolus, nuclear speckles, paraspeckles, promyelocytic leukemia (PML) bodies, Cajal bodies (all exert crucial roles in cellular physiology), and evidence are emerging day by day. Also, phase separation is well documented in generation of plasma membrane subdomains and interplay between membranous and membraneless organelles. Intrinsically disordered regions (IDRs) of biopolymers/proteins are the most critical sticking regions that aggravate the formation of such condensates. Remarkably, phase separated condensates are also involved in epigenetic regulation of gene expression, chromatin remodeling, and heterochromatinization. Epigenetic marks on DNA and histones cooperate with RNA-binding proteins through their IDRs to trigger LLPS for facilitating transcription. How phase separation coalesces mutant oncoproteins, orchestrate tumor suppressor genes expression, and facilitated cancer-associated signaling pathways are unravelling. That autophagosome formation and DYRK3-mediated cancer stem cell modification also depend on phase separation is deciphered in part. In view of this, and to linchpin insight into the subcellular membraneless organelle assembly, gene activation and biological reactions catalyzed by enzymes, and the downstream physiological functions, and how all these events are precisely facilitated by LLPS inducing organelle function, epigenetic modulation of gene expression in this scenario, and how it goes awry in cancer progression are summarized and presented in this article. [Display omitted] • LLPS defines macromolecular assemblies, membraneless organelles and biochemical processes. • IDR, LCR, lncRNA and multivalent domain-motif interactions drive LLPS formation. • LLPS regulates chromatin organization and gene expression. • LLPS influence cancer, cancer associated signaling, autophagy and apoptosis. • Machine learning is applicable to predict phase separation and multiple interactions in LLPS. [ABSTRACT FROM AUTHOR]

Epigenomic and metabolic changes impact retinal health and disease. Metabolite levels influence key epigenomic changes that regulate the retinal transcriptome. Epigenome-metabolism crosstalk underlies retinal adaptation to aging and the environment. The epigenome–metabolism nexus suggests interventions for retinal diseases. Intimate links between epigenome modifications and metabolites allude to a crucial role of cellular metabolism in transcriptional regulation. Retina, being a highly metabolic tissue, adapts by integrating inputs from genetic, epigenetic, and extracellular signals. Precise global epigenomic signatures guide development and homeostasis of the intricate retinal structure and function. Epigenomic and metabolic realignment are hallmarks of aging and highlight a link of the epigenome–metabolism nexus with aging-associated multifactorial traits affecting the retina, including age-related macular degeneration and glaucoma. Here, we focus on emerging principles of epigenomic and metabolic control of retinal gene regulation, with emphasis on their contribution to human disease. In addition, we discuss potential mitigation strategies involving lifestyle changes that target the epigenome-metabolome relationship for maintaining retinal function. [ABSTRACT FROM AUTHOR]

To initiate var gene activation, the active var gene must relocate to a specific site at the nuclear periphery dedicated to singular gene expression. Noncoding RNA associated with this site serves as a scaffold, recruiting essential proteins required for facilitating var gene expression. Research on the interactome of noncoding RNA (ncRNA) has identified enzymes and chromatin factors involved in the exclusive expression of individual var genes. External influences can impede the expression of var genes by suppressing the RUF6 noncoding RNA family through RNA polymerase III (Pol III). In individuals experiencing asymptomatic malaria during the dry season in The Gambia, decreased activity of Pol III in Plasmodium falciparum has been observed. The protozoan parasite Plasmodium falciparum , responsible for the deadliest form of human malaria, employs antigenic variation via monoallelic expression as a key survival strategy. The selective activation of one out of the 60-member var gene family is key to understanding the parasite's ability to cause severe disease and evade the host immune response. var gene activation is initiated by its relocation to a specialized expression site. While the perinuclear expression site (PES) plays a crucial role in enabling the expression of a single allele, the characteristics of this PES remain largely obscure. Recent breakthroughs in genome editing tools and the discovery of regulatory noncoding RNAs have shed light on this intriguing biological feature, offering significant insights into the mechanisms of pathogen virulence. [ABSTRACT FROM AUTHOR]

Schizophrenia is a polygenic complex disease with a heritability as high as 80 %, yet the mechanism of polygenic interaction in its pathogenesis remains unclear. Studying the interaction and regulation of schizophrenia susceptibility genes is crucial for unraveling the pathogenesis of schizophrenia and developing antipsychotic drugs. Therefore, we developed a bioinformatics method named GRACI (Gene Regulation Analysis based on Causal Inference) based on the principles of information theory, a causal inference model, and high order chromatin 3D conformation. GRACI captures the interaction and regulatory relationships between schizophrenia susceptibility genes by analyzing genotyping data. Two datasets, comprising 1459 and 2065 samples respectively, were analyzed, and the gene networks from both datasets were constructed. GRACI showcased superior accuracy when compared to widely adopted methods for detecting gene-gene interactions and intergenic regulation. This alignment was further substantiated by its correlation with chromatin high-order conformation patterns. Using GRACI, we identified three potential genes— KCNN3 , KCNH1 , and KCND3 —that are directly associated with schizophrenia pathogenesis. Furthermore, the results of GRACI on the standalone dataset illustrated the method's applicability to other complex diseases. GRACI download: https://github.com/liuliangjie19/GRACI [ABSTRACT FROM AUTHOR]

Components of the Hippo kinase module are present in some unicellular organisms, and unicellular orthologs of the Hippo pathway kinase Warts have the capability to phosphorylate Yorkie, despite the absence of Yorkie in many of these organisms. A complete core Hippo pathway, including the transcriptional coactivator Yorkie, predated the origin of animals, and is present in the closest unicellular relatives of animals. Functional studies in unicellular organisms and early-branching animals suggest that an ancestral function of the Hippo pathway was regulation of the actomyosin cytoskeleton, and that the pathway was subsequently co-opted for tissue size regulation in the lineage leading to bilaterian animals. Acquisition of the ability of Yorkie to regulate cell proliferation and tissue size regulation may have coincided with the evolutionary emergence of distal enhancer-mediated gene regulation in animals. Decades of work in developmental genetics has given us a deep mechanistic understanding of the fundamental signaling pathways underlying animal development. However, little is known about how these pathways emerged and changed over evolutionary time. Here, we review our current understanding of the evolutionary emergence of the Hippo pathway, a conserved signaling pathway that regulates tissue size in animals. This pathway has deep evolutionary roots, emerging piece by piece in the unicellular ancestors of animals, with a complete core pathway predating the origin of animals. Recent functional studies in close unicellular relatives of animals and early-branching animals suggest an ancestral function of the Hippo pathway in cytoskeletal regulation, which was subsequently co-opted to regulate proliferation and animal tissue size. Decades of work in developmental genetics has given us a deep mechanistic understanding of the fundamental signaling pathways underlying animal development. However, little is known about how these pathways emerged and changed over evolutionary time. Here, we review our current understanding of the evolutionary emergence of the Hippo pathway, a conserved signaling pathway that regulates tissue size in animals. This pathway has deep evolutionary roots, emerging piece by piece in the unicellular ancestors of animals, with a complete core pathway predating the origin of animals. Recent functional studies in close unicellular relatives of animals and early-branching animals suggest an ancestral function Hippo pathway of cytoskeletal regulation, which was subsequently co-opted to regulate proliferation and animal tissue size. [ABSTRACT FROM AUTHOR]

Genetic circuits can endow microbial cell factories with the ability for self-learning and decision-making. Many standardized formats or automated software are developed to design genetic circuits. Many methods are developed to select and construct genetic parts. Recent advances in synthetic biology have provided a toolbox for constructing high-performance genetic circuits. Genetic circuits are widely employed for the dynamic regulation of metabolic networks and high-throughput screening of overproducers. In recent years, genetic circuit-based regulation of metabolic flux in microbial cell factories has received significant attention. In this review, we describe a pipeline for the design and construction of genetic circuits for metabolic flux optimization. In particular, we summarize the recent advances in computationally assisted prediction of critical metabolic nodes and genetic circuit design automation. Further, we introduce strategies for constructing high-performance genetic circuits. We also summarize the latest applications of genetic circuits in the dynamic regulation of metabolism and high-throughput screening. Finally, we discuss the challenges and prospects associated with the design and construction of sophisticated genetic circuits. Through this review, we aim to provide a theoretical basis for designing and constructing high-performance genetic circuits to optimize metabolic flux. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) poses significant therapeutic challenges, particularly OA that affects the hand. Currently available treatment strategies are often limited in terms of their efficacy in managing pain, regulating invasiveness, and restoring joint function. The APRICOTⓇ implant system developed by Aurora Medical Ltd (Chichester, UK) introduces a minimally invasive, bone-conserving approach for treating hand OA (https://apricot-project.eu/). By utilizing polycarbonate urethane (PCU), this implant incorporates a caterpillar track-inspired design to promote the restoration of natural movement to the joint. Surface modifications of PCU have been proposed for the biological fixation of the implant. This study investigated the biocompatibility of PCU alone or in combination with two surface modifications, namely dopamine-carboxymethylcellulose (dCMC) and calcium-phosphate (CaP) coatings. In a rat soft tissue model, native and CaP-coated PCU foils did not increase cellular migration or cytotoxicity at the implant–soft tissue interface after 3 d, showing gene expression of proinflammatory cytokines similar to that in non-implanted sham sites. However, dCMC induced an amplified initial inflammatory response that was characterized by increased chemotaxis and cytotoxicity, as well as pronounced gene activation of proinflammatory macrophages and neoangiogenesis. By 21 d, inflammation subsided in all the groups, allowing for implant encapsulation. In a rat bone model, 6 d and 28 d after release of the periosteum, all implant types were adapted to the bone surface with a surrounding fibrous capsule and no protracted inflammatory response was observed. These findings demonstrated the biocompatibility of native and CaP-coated PCU foils as components of APRICOTⓇ implants. Hand osteoarthritis treatments require materials that minimize irritation of the delicate finger joints. Differing from existing treatments, the APRICOTⓇ implant leverages polycarbonate urethane (PCU) for minimally invasive joint replacement. This interdisciplinary, preclinical study investigated the biocompatibility of thin polycarbonate urethane (PCU) foils and their surface modifications with calcium-phosphate (CaP) or dopamine-carboxymethylcellulose (dCMC). Cellular and morphological analyses revealed that both native and Ca-P coated PCU elicit transient inflammation, similar to sham sites, and a thin fibrous encapsulation in soft tissues and on bone surfaces. However, dCMC surface modification amplified initial chemotaxis and cytotoxicity, with pronounced activation of proinflammatory and neoangiogenesis genes. Therefore, native and CaP-coated PCU possess sought-for biocompatible properties, crucial for patient safety and performance of APRICOTⓇ implant. [Display omitted] [ABSTRACT FROM AUTHOR]

• Gamma irradiation's efficacy for inducing beneficial genomic changes. • Transcriptome data revealed 351 upregulated DEGs in Fusarium tolerant Himgiri-17.5. • R -genes were expressed in Himgiri-17.5 contributing to Fusarium wilt resistance. • Mapped 14 indels linked to R -genes could be implicated for marker assisted selection. • Identified transcription factors suggest role in defense gene expression regulation. Zingiber officinale Rosc. is a significant perennial herbaceous plant referred as 'universal medicine' in Ayurveda , due to its wide range of medicinal properties. It is vegetatively propagated via rhizomes, rendering it vulnerable to numerous pathogens found in soil, amongst which Fusarium oxysporum f.sp. zingiberi has emerged as a major fungal pathogen accountable for rhizome & soft rot, and Fusarium yellows, leading to substantial loss. To overcome this problem, Fusarium wilt tolerant ginger 'Himgiri-17.5′ was developed employing in vitro induction of mutations and selection technique. Its transcriptome analysis in comparison with traditionally propagated 'Himgiri' was performed aimed to identify crucial defense-related genes and the role they play in plant-pathogen interaction. Illumina paired-end sequencing resulted in 57,939 annotated transcripts, amongst which 3745 were differentially expressed genes (DEGs) with 351 up-regulated. Fifty three DEGs, exclusively related to disease resistance (R) proteins spanning diverse domains, including transmembrane, kinases, nucleotide-binding site, leucine-rich repeats, coiled-coil, and Toll/Interleukin-1 receptors were identified in Himgiri-17.5. Functional annotation revealed the involvement of DEGs in positive regulation of transcription and response to pathogenic stimuli, emphasizing their role in plant defense mechanism. Fourteen indels associated with R -genes were also mapped on various chromosomes, representing invaluable genetic markers to identify genomic regions affiliated to disease resistance to serve as potential targets for genetic modification and marker-assisted selection. In addition, the analysis identified 165 up-regulated transcription factors, including v-Myb myeloblastosis viral oncogene homolog (MYB) and ethylene responsive factor (ERF) families, indicates their possible part in governing gene expression during defense mechanism. This research contributes in understanding the key genetic aspects including R -genes, indels, and transcription factors associated with pathogen recognition, signal transduction, and defense responses crucial for Fusarium wilt tolerance and holds the foundation for future studies to enhance disease resistance through biotechnological interventions. [ABSTRACT FROM AUTHOR]

RNA profiling studies have revealed that ∼75% of the human genome is transcribed to RNA but only a meagre fraction of it is translated to proteins. Majority of transcribed RNA constitute a specialized pool of non-coding RNAs. Human genome contains approximately 506 genes encoding a set of 51 different tRNAs, constituting a unique class of non-coding RNAs that not only have essential housekeeping functions as translator molecules during protein synthesis, but have numerous uncharted regulatory functions. Intriguing findings regarding a variety of non-canonical functions of tRNAs, tRNA derived fragments (tRFs), esoteric epitranscriptomic modifications of tRNAs, along with aminoacyl-tRNA synthetases (AARSs) and ARS-interacting multifunctional proteins (AIMPs), envision a 'peripheral dogma' controlling the flow of genetic information in the backdrop of qualitative information wrung out of the long-live central dogma of molecular biology, to drive cells towards either proliferation or differentiation programs. Our review will substantiate intriguing peculiarities of tRNA gene clusters, atypical tRNA-transcription from internal promoters catalysed by another distinct RNA polymerase enzyme, dynamically diverse tRNA epitranscriptome, intricate mechanism of tRNA-charging by AARSs governing translation fidelity, epigenetic regulation of gene expression by tRNA fragments, and the role of tRNAs and tRNA derived/associated molecules as quantitative determinants of the functional proteome, covertly orchestrating the process of tumorigenesis, through a deregulated tRNA-ome mediating selective codon-biased translation of cancer related gene transcripts. [Display omitted] • Distinct tRNA repertoire undertakes codon-biased translation of cancer linked genes. • tRNA deregulation & mischarging diversify tumor proteome entailing chemo-resistance. • Deregulated 'writers' alter the epitranscriptome & stabilize cancerous tRNA profile. • As part of MSC, AARS-AIMPs play non-canonical oncogenic/tumor-suppressive roles. • tRFs/tRDs fine-tune epigenetic regulation of genes involved in tumour progression. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small highly conserved non-coding RNA molecules that orchestrate a wide range of biological processes through post-transcriptional regulation of gene expression. During development, miRNAs play a key role in driving embryo patterning and morphogenesis in a specific and stage-dependent manner. Here, we investigated whether sperm from bulls with different fertilizing ability in vitro influence blastocyst quality and miRNA content. Results demonstrate that blastocysts obtained using sperm from high fertility sires (H group) display significantly greater cleavage and blastocyst development as well as greater transcript abundance in blastocysts for the developmental competence markers CDX2 , KRT8 , NANOG , OCT4 , PLAC8 , PTGS2 , SOX17 , and SOX2 , compared to blastocysts generated using sperm from low fertility sires (L group). In parallel, high throughput deep sequencing and differential expression studies revealed that H blastocysts exhibit a greater miRNA content compared to L blastocysts, with hsa-miR-4755–5p and hsa-miR-548d-3p uniquely detected in the H group, and greater abundance of hsa-miR-1225–3p in the H group. Gene ontology (GO) and KEGG pathway analyses indicated that the 3 differentially expressed miRNAs identified are involved in the regulation of many biological mechanisms with a key role in aspects of early embryo development, including transcriptional regulation, cellular biosynthesis, nucleic acid metabolism, cellular differentiation, apoptosis, cytoskeleton remodeling, cell-to-cell interactions, and endocytosis. Overall, our results indicate that sperm fertilizing ability influences blastocyst developmental ability and miRNA content. In addition, we demonstrate an association between blastocyst quality and miRNA content, thus suggesting the possibility to score miRNA expression as biomarkers for improved routine embryo selection technologies to support assisted reproductive efforts. • Sperm fertilizing ability influences blastocyst developmental ability and miRNA content. • Paternal influence extends its effects through early embryogenesis and may impact on the further development. • Blastocysts obtained from H group exhibit a greater miRNA content compared to blastocysts obtained from Lgroup. • Differentially expressed miRNAs are involved in the regulation of many biological mechanisms with a key role in aspects of early embryo development. [ABSTRACT FROM AUTHOR]

Primordial germ cells (PGCs) are the precursors of germ cells and play a crucial role in germline transmission. In chickens, PGCs can be cultured in vitro while maintaining their germline stem cell characteristics. The Deleted in Azoospermia-Like (DAZL) gene, which is highly expressed in PGCs, is essential for germ cell development. Here, through gene knockout experiments, we discovered that the loss of DAZL expression in chicken PGCs led to decreased proliferation and survival. By next employed techniques such as RIP-seq (RNA Binding Protein Immunoprecipitation) and Co-IP-MS/MS (Co-immunoprecipitation Mass Spectrometry), we identified genes directly regulated by DAZL or cooperating with DAZL at the transcriptomic and proteomic levels. DAZL was found to control genes related to germline development, pluripotency, and cell proliferation in PGCs. Additionally, we observed a significant overlap between RNAs and proteins that interact with both DAZL and DDX4, indicating their cooperation in the gene regulation network in chicken PGCs. Our research provides valuable insights into the function of the DAZL gene in germline cells. [ABSTRACT FROM AUTHOR]

Gene regulatory network (GRN) comprises complicated yet intertwined gene-regulator relationships. Understanding the GRN dynamics will unravel the complexity behind the observed gene expressions. Insect gene regulation is often complicated due to their complex life cycles and diverse ecological adaptations. The main interest of this review is to have an update on the current mathematical modelling methods of GRNs to explain insect science. Several popular GRN architecture models are discussed, together with examples of applications in insect science. In the last part of this review, each model is compared from different aspects, including network scalability, computation complexity, robustness to noise and biological relevancy. [Display omitted] [ABSTRACT FROM AUTHOR]

Gene therapy is a fast-growing field showing great potential to treat genetic diseases and cancer. With accelerating gene therapy development and approval, their environment risk assessment (ERA) becomes increasingly important. An ERA is an assessment of the risks to human health and the environment upon exposure to a medicinal product as the result of its release during clinical development or after entering the market. Because ERA is an important component of regulatory submission, drug developers must perform a robust assessment to ensure the safety of unintended persons, animal, plants, microorganisms and environment at large. Global regulations on gene therapy ERA continue to evolve. Gene therapy ERAs are carried out according to general principles as provided in regulatory guidelines for application of clinical trials and marketing authorizations. The current review intends to summarize regulations and content requirements on gene therapy ERA in European Union, the USA and Japan. The approved gene therapy products by EMA and US Food and Drug Administration are analyzed for the critical aspects of their ERAs to provide the current status and practice of gene therapy ERAs by drug developers. For this purpose, the main contents of these gene therapy ERAs are summarized. Critical safety factors of gene therapy ERAs are described. With more experience and knowledge to be accumulated, gene therapy ERAs are expected to be less challenging with commonly used viral vectors. [ABSTRACT FROM AUTHOR]

The root angle in cereals determines soil resource capture, stress resilience, and yield, especially in suboptimal conditions. Root angle regulation involves competing gravitropic and antigravitropic offset mechanisms. Understanding the mechanisms underlying root angle regulation in cereals is important due to their complex root system made up of distinct root types, formed at different stages of development. Recent studies in cereals revealed genes regulating the root angle. However, the precise mechanisms determining and maintaining root angle in distinct root types remain unclear. Understanding the molecular mechanisms underlying root angle control is essential for incorporating the root angle trait into breeding programs. The root angle plays a critical role in efficiently capturing nutrients and water from different soil layers. Steeper root angles enable access to mobile water and nitrogen from deeper soil layers, whereas shallow root angles facilitate the capture of immobile phosphorus from the topsoil. Thus, understanding the genetic regulation of the root angle is crucial for breeding crop varieties that can efficiently capture resources and enhance yield. Moreover, this understanding can contribute to developing varieties that effectively sequester carbon in deeper soil layers, supporting global carbon mitigation efforts. Here we review and consolidate significant recent discoveries regarding the molecular components controlling root angle in cereal crop species and outline the remaining research gaps in this field. [ABSTRACT FROM AUTHOR]

The methylotrophic yeast Komagataella phaffii is a popular host system for the pharmaceutical and biotechnological production of recombinant proteins. CRISPR-Cas9 and its derivative CRISPR interference (CRISPRi) offer a promising avenue to further enhance and exploit the full capabilities of this host. MAD7 and its catalytically inactive variant "dead" MAD7 (dMAD7) represent an interesting alternative to established CRISPR-Cas9 systems and are free to use for industrial and academic research. CRISPRi utilizing dMAD7 does not introduce double-strand breaks but only binds to the DNA to regulate gene expression. Here, we report the first use of dMAD7 in K. phaffii to regulate the expression of the enhanced green fluorescent protein (eGFP). A reduction of eGFP fluorescence level (up to 88 %) was achieved in random integration experiments using dMAD7 plasmids. Integration loci/events of investigated strains were assessed through whole genome sequencing. Additionally, RNA-sequencing experiments corroborated the whole genome sequencing results and showed a significantly reduced expression of eGFP in strains containing a dMAD7 plasmid, among others. Our findings conclusively demonstrate the utility of dMAD7 in K. phaffii through successfully regulating eGFP expression. • We report the first use of dMAD7 in K. phaffii to regulate the expression of enhanced green fluorescent protein (eGFP). • A reduction of eGFP fluorescence level (up to 88 %) was achieved in random integration experiments using dMAD7 plasmids. • Whole genome sequencing and RNA-sequencing were used to assess the integration events and to characterize the strains. • Our findings conclusively demonstrate the utility of the dMAD7 system in K. phaffii. [ABSTRACT FROM AUTHOR]

The tailor-made synthetic sRNA-based gene expression knockdown system has demonstrated its efficacy in achieving pathway balancing in microbes, facilitating precise target gene repression and fine-tuned control of gene expression. This system operates under a competitive mode of gene regulation, wherein the tailor-made synthetic sRNA shares the intrinsic intracellular Hfq protein with other RNAs. The limited intracellular Hfq amount has the potential to become a constraining factor in the post-transcription regulation of sRNAs. To enhance the efficiency of the tailor-made sRNA gene expression regulation platform, we introduced an Hfq expression level modulation-coordinated sRNA-based gene knockdown system. This system comprises tailor-made sRNA expression cassettes that produce varying Hfq expression levels using different strength promoters. Modulating the expression levels of Hfq significantly improved the repressing capacity of sRNA, as evidenced by evaluations with four fluorescence proteins. In order to validate the practical application of this system, we applied the Hfq-modulated sRNA-based gene knockdown cassette to Escherichia coli strains producing 5-aminolevulinic acid and L-tyrosine. Diversifying the expression levels of metabolic enzymes through this cassette resulted in substantial increases of 74.6% in 5-aminolevulinic acid and 144% in L-tyrosine production. Tailor-made synthetic sRNA-based gene expression knockdown system, coupled with Hfq copy modulation, exhibits potential for optimizing metabolic fluxes through biosynthetic pathways, thereby enhancing the production yields of bioproducts. • sRNA system suppresses gene expression, utilizing intrinsic Hfq proteins shared with other RNAs. • Adjusting the Hfq quantity facilitates effective repression of gene expression through sRNA. • The application showed elevated 5-aminolevulnic acid (74.6%) and L-tyrosine (144%) production. [ABSTRACT FROM AUTHOR]

The variety and efficiency of tools and strategies to genetically engineer microalgae have significantly increased within the last decade. Several alternative production concepts have been developed in microalgae, highlighting the industrial potential of these organisms for sustainable bioproduction. Yet, low product titers limit the economic feasibility in many cases. The 2-C-methyl-D-erythritol 4-phosphate (MEP) and the fatty acid synthesis pathway provide sufficient valuable metabolites to produce required terpenoids, carotenoids, as well as lipids and (modified) fatty acids. The ensuing aim for microalgal biotechnology is to strategically combine potent genetic engineering tools and improved cultivation strategies to achieve high product titers that enable economic viability. Microalgae are regarded as sustainable and potent chassis for biotechnology. Their capacity for efficient photosynthesis fuels dynamic growth independent from organic carbon sources and converts atmospheric CO 2 directly into various valuable hydrocarbon-based metabolites. However, approaches to gene expression and metabolic regulation have been inferior to those in more established heterotrophs (e.g., prokaryotes or yeast) since the genetic tools and insights in expression regulation have been distinctly less advanced. In recent years, however, these tools and their efficiency have dramatically improved. Various examples have demonstrated new trends in microalgal biotechnology and the potential of microalgae for the transition towards a sustainable bioeconomy. [ABSTRACT FROM AUTHOR]

The postnatal brain undergoes chromatin and transcriptional changes that underlie functional maturation (e.g., electrophysiological properties, morphology, connectivity, network activity) across the lifespan. While these changes are observed across the animal kingdom, changes associated with maturation, including timing, are often neuron-type, brain-region, and species specific. Sensory stimulus coordination of neuronal activity and cross-modal neurotransmission is one mechanism by which the external environment regulates neuronal maturation. Neuronal activity controls the molecular changes underlying neuronal maturation by regulating transcriptional and chromatin factors. Aspects of postnatal neuronal maturation are regulated by cell-intrinsic sensory stimulus-independent genetic timer cascades. These mechanisms are intertwined with cell-extrinsic mechanisms to control maturation. Embryonic neurodevelopment, particularly neural progenitor differentiation into post-mitotic neurons, has been extensively studied. While the number and composition of post-mitotic neurons remain relatively constant from birth to adulthood, the brain undergoes significant postnatal maturation marked by major property changes frequently disrupted in neural diseases. This review first summarizes recent characterizations of the functional and molecular maturation of the postnatal nervous system. We then review regulatory mechanisms controlling the precise gene expression changes crucial for the intricate sequence of maturation events, highlighting experience-dependent versus cell-intrinsic genetic timer mechanisms. Despite significant advances in understanding of the gene-environmental regulation of postnatal neuronal maturation, many aspects remain unknown. The review concludes with our perspective on exciting future research directions in the next decade. [ABSTRACT FROM AUTHOR]

In this paper, the most probable exit path is applied to understand the switching of a bistable synthetic gene network with genetic toggle in Escherichia coli from a new perspective. It is worth mentioning that the most probable exit path is a deterministic indicator for researching stochastic system, and its role is analogous to the phase diagram and time history diagram of deterministic system. Firstly, the large deviation theory proves that when a dynamic system has a stable equilibrium point, the cumulative effect of its long-term action can make its sample trajectory reach another region with a probability of 1 from the attractive region under weak random disturbance. The concept of the most probable exit path is given by defining Freidlin-Wentzell action functional. Moreover, considering the noise intensity, Onsager-Machlup action functional is defined to obtain the most probable exit path of the system subject to random disturbance. Based on the Onsager-Machlup action functional, it can be observed that the impact of two types of noise intensities on the most probable exit path for the transition of the system. In addition, based on vector field decomposition, energy landscape is used to analyze the global stability of the system. Finally, this article intuitively demonstrates the switching process of the system with genetic toggle. The analysis of Onsager-Machlup action functional reveals that two independent noises have opposite effects on the system switching. The increase in the intensity of the second Gaussian noise is conductive to more accurately observing the most probable exit path of the system. According to the energy landscape, the reduction of noise intensity is not conductive to switching of the system with genetic toggle. • Most probable exit path intuitively illustrates the process of stochastic gene regulation. • Most probable exit path is obtained using FW and OM functional respectively by large deviation theory. • Analyze the effects of noise intensity and final time, provide guidance for gene expression cell differentiation process. • Based on vector field decomposition, energy landscape is used for global stability analysis of the system. [ABSTRACT FROM AUTHOR]

Obesity-induced metabolic dysfunction-associated steatohepatitis (MASH) leads to hepatocellular carcinoma (HCC). Astrocyte-elevated gene-1/Metadherin (AEG-1/MTDH) plays a key role in promoting MASH and HCC. AEG-1 is palmitoylated at residue cysteine 75 (Cys75) and a knock-in mouse representing mutated Cys75 to serine (AEG-1-C75S) showed activation of MASH- and HCC-promoting gene signature when compared to wild-type littermates (AEG-1-WT). The liver consists of three zones, periportal, mid-lobular, and pericentral, and zone-specific dysregulated gene expression impairs metabolic homeostasis in the liver, contributing to MASH and HCC. Here, to elucidate how palmitoylation influences AEG-1-mediated gene regulation in regard to hepatic zonation, we performed spatial transcriptomics (ST) in the livers of AEG-1-WT and AEG-1-C75S littermates. ST identified six different clusters in livers and using zone- and cell-type-specific markers we attributed specific zones and cell types to specific clusters. Ingenuity Pathway Analysis (IPA) of differentially expressed genes in each cluster unraveled activation of pro-inflammatory and MASH- and HCC-promoting pathways, mainly in periportal and pericentral hepatocytes, in AEG-1-C75S liver compared to AEG-1-WT. Interestingly, in AEG-1-C75S liver, the mid-lobular zone exhibited widespread inhibition of xenobiotic metabolism pathways and inhibition of PXR/RXR and LXR/RXR activation, versus AEG-1-WT. In conclusion, AEG-1-C75S mutant exhibited zone-specific differential gene expression, which might contribute to metabolic dysfunction and dysregulated drug metabolism leading to MASH and HCC. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress, a common cellular stress response induced by various factors that interfere with cellular homeostasis, may trigger cell apoptosis. Autophagy is an important and conserved mechanism for eliminating aggregated proteins and maintaining protein stability of cells, which is closely associated with ER stress and ER stress–induced apoptosis. In this paper, we report for the first time that Hhatl, an ER-resident protein, is downregulated in response to ER stress. Hhatl overexpression alleviated ER stress and ER stress induced apoptosis in cells treated with tunicamycin or thapsigargin, whereas Hhatl knockdown exacerbated ER stress and apoptosis. Further study showed that Hhatl attenuates ER stress by promoting autophagic flux. Mechanistically, we found that Hhatl promotes autophagy by associating with autophagic protein LC3 (microtubule-associated protein 1A/1B-light chain 3) via the conserved LC3-interacting region motif. Noticeably, the LC3-interacting region motif was essential for Hhatlregulated promotion of autophagy and reduction of ER stress. These findings demonstrate that Hhatl ameliorates ER stress via autophagy activation by interacting with LC3, thereby alleviating cellular pressure. The study indicates that pharmacological or genetic regulation of Hhatl-autophagy signaling might be potential for mediating ER stress and related diseases. [ABSTRACT FROM AUTHOR]

The myocyte enhancer factor (MEF2) family of transcription factors, originally discovered for its pivotal role in muscle development and function, has emerged as an essential regulator in various aspects of brain development and neuronal plasticity. The MEF2 transcription factors are known to regulate numerous important genes in the nervous system, including brain-derived neurotrophic factor (BDNF), a small secreted neurotrophin responsible for promoting the survival, growth, and differentiation of neurons. The expression of the Bdnf gene is spatiotemporally controlled by various transcription factors binding to both its proximal and distal regulatory regions. While previous studies have investigated the connection between MEF2 transcription factors and Bdnf, the endogenous function of MEF2 factors in the transcriptional regulation of Bdnf remains largely unknown. Here, we aimed to deepen the knowledge of MEF2 transcription factors and their role in the regulation of Bdnf comparatively in rat cortical and hippocampal neurons. As a result, we demonstrate that the MEF2 transcription factor-dependent enhancer located at −4.8 kb from the Bdnf gene regulates the endogenous expression of Bdnf in hippocampal neurons. In addition, we confirm neuronal activity-dependent activation of the −4.8 kb enhancer in vivo. Finally, we show that specific MEF2 family transcription factors have unique roles in the regulation of Bdnf, with the specific function varying based on the particular brain region and stimuli. Altogether, we present MEF2 family transcription factors as crucial regulators of Bdnf expression, finetuning Bdnf expression through both distal and proximal regulatory regions. [ABSTRACT FROM AUTHOR]

Insights into the evolution of regulatory networks are emerging from studies of the 3D structure of chromatin and its role in transcriptional regulation. The development of regulome technologies has advanced our understanding of the evolutionary principles governing regulatory elements and chromatin organization. Transposons have had an important role in the evolution of cis -regulatory element (CRE) landscapes, including the formation of novel CREs and the alteration of distances between CREs and genes. The dynamics of hierarchical chromatin organization, driven by genetic variation, emerges as a critical factor in the evolution of gene regulation. This offers a promising framework for investigating the evolution of regulatory mechanisms in plant systems, their differences among species and genotypes, and following polyploidy. Development of complex traits necessitates the functioning and coordination of intricate regulatory networks involving multiple genes. Understanding 3D chromatin structure can facilitate insight into the regulation of gene expression by regulatory elements. This potential, of visualizing the role of chromatin organization in the evolution and function of regulatory elements, remains largely unexplored. Here, we describe new perspectives that arise from the dual considerations of sequence variation of regulatory elements and chromatin structure, with a special focus on whole-genome doubling or polyploidy. We underscore the significance of hierarchical chromatin organization in gene regulation during evolution. In addition, we describe strategies for exploring chromatin organization in future investigations of regulatory evolution in plants, enabling insights into the evolutionary influence of regulatory elements on gene expression and, hence, phenotypes. [ABSTRACT FROM AUTHOR]

Pathophysiological hallmarks of Alzheimer's disease (AD) include extracellular amyloid plaques and intracellular neurofibrillary tangles. Recent studies also demonstrated a role of neuroinflammation in the progression of the disease. Clinical trials and animal studies using low-dose radiation therapy (LDRT) have shown therapeutic potential for AD. This systematic review summarizes the current evidence on the use of LDRT for the treatment of AD, outlines potential mechanisms of action, and discusses current challenges in the planning of future trials. A systematic review of human and animal studies as well as registered clinical trials describing outcomes for RT in the treatment of AD was conducted. We followed the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles published until July 1, 2023, were included. The initial search yielded 993 articles. After the removal of duplicates and ineligible publications, a total of 16 (12 animal, 4 human) studies were included. Various dose regimens were utilized in both animal and human trials. The results revealed that LDRT reduced the number of amyloid plaques and neurofibrillary tangles, and it has a role in the regulation of genes and protein expression involved in the pathological progression of AD. LDRT has demonstrated reduced astro- and microgliosis, anti-inflammatory and neuroprotective effects, and an alleviation of symptoms of cognitive deficits in animal models. Most studies in humans suggested improvements in cognition and behavior. None of the trials or studies described significant (>grade 2) toxicity. Preclinical studies, animal studies, and early clinical trials in humans have shown a promising role for LDRT in the treatment of AD pathologies, although the underlying mechanisms are yet to be fully explored. Phase I/II/III trials are needed to assess the long-term safety, efficacy, and optimal treatment parameters of LDRT in AD treatment. [ABSTRACT FROM AUTHOR]

Helitrons are notoriously difficult to identify, due to low conservation of their internal sequences and few characteristic sequence features. New sequencing technologies and genome analysis tools open advanced possibilities for the identification of Helitrons, allowing one to monitor Helitron activity and its consequences. Helitrons can transpose gene fragments, including regulatory elements of genes, thereby creating new circuits of gene regulation. In plants, this has been demonstrated for endosperm-specific regulatory elements and elements regulating the response to herbivores, but more examples are likely to be discovered. Helitron-captured gene fragments can elicit evolutionary conflicts. This is because the host silencing machinery will target the Helitron and the captured gene, causing transacting silencing effects on the donor gene. Helitrons, classified as DNA transposons, employ rolling-circle intermediates for transposition. Distinguishing themselves from other DNA transposons, they leave the original template element unaltered during transposition, which has led to their characterization as 'peel-and-paste elements'. Helitrons possess the ability to capture and mobilize host genome fragments, with enormous consequences for host genomes. This review discusses the current understanding of Helitrons, exploring their origins, transposition mechanism, and the extensive repercussions of their activity on genome structure and function. We also explore the evolutionary conflicts stemming from Helitron-transposed gene fragments and elucidate their domestication for regulating responses to environmental challenges. Looking ahead, further research in this evolving field promises to bring interesting discoveries on the role of Helitrons in shaping genomic landscapes. [ABSTRACT FROM AUTHOR]

Poly(UG) or 'pUG' dinucleotide repeats direct gene silencing in Caenorhabditis elegans by adopting an unusual quadruplex structure. Humans have thousands of pUG sequences and proteins that interact with them. The pUG fold reveals new aspects of gene regulation and RNA folding, highlighting how a simple sequence can encode a complex structure. [ABSTRACT FROM AUTHOR]

Light and temperature sensing are important features of many organisms. Light may provide energy but may also be used by non-photosynthetic organisms for orientation in the environment. Recent evidence suggests that plant and fungal phytochrome and plant phototropin serve dual functions as light and temperature sensors. Here we characterized the fungal LOV-domain blue-light receptor LreA of Alternaria alternata and show that it predominantly contains FAD as chromophore. Blue-light illumination induced ROS production followed by protein agglomeration in vitro. In vivo ROS may control LreA activity. LreA acts as a blue-light photoreceptor but also triggers temperature-shift-induced gene expression. Both responses required the conserved amino acid cysteine 421. We therefore propose that temperature mimics the photoresponse, which could be the ancient function of the chromoprotein. Temperature-dependent gene expression control with LreA was distinct from the response with phytochrome suggesting fine-tuned, photoreceptor-specific gene regulation. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms exert control over secondary metabolite production by modulating chromatin conformation to govern transcriptional activity. Arabidopsis (Arabidopsis thaliana) flowering time gene regulation provides a valuable model for studying transcriptional and epigenetic regulation at the chromatin level. Multivalent biomolecular interactions also play a pivotal role in the function of transcription and epigenetic factors, making a significant contribution to the regulation of gene expression and dynamic chromatin modifications. Emerging research from the pioneer transcription factor, noncoding RNA, and RNA structure fields offers fresh insights that could refine current understanding of metabolic pathway regulation. Further investigation into the transcriptional and epigenetic regulation of secondary metabolism is necessary to bridge the current knowledge gap that exists between resource plants and the model species A. thaliana. Secondary metabolite (SM) production provides biotic and abiotic stress resistance and enables plants to adapt to the environment. Biosynthesis of these metabolites involves a complex interplay between transcription factors (TFs) and regulatory elements, with emerging evidence suggesting an integral role for chromatin dynamics. Here we review key TFs and epigenetic regulators that govern SM biosynthesis in different contexts. We summarize relevant emerging technologies and results from the model species arabidopsis (Arabidopsis thaliana) and outline aspects of regulation that may also function in food, feed, fiber, oil, or industrial crop plants. Finally, we highlight how effective translation of fundamental knowledge from model to non-model species can benefit understanding of SM production in a variety of ecological, agricultural, and pharmaceutical contexts. [ABSTRACT FROM AUTHOR]

Specialized metabolic pathways are highly regulated. This regulation includes feedback inhibition of the transcriptional machinery by pathway intermediates or products. Specialized metabolites can be sensed by numerous mechanisms, impacting multiple levels of transcriptional regulation, thus leading to major changes in gene expression. The regulatory effect of specialized metabolites involves other aspects of gene expression, in addition to transcription. Recent advances in our understanding of plant metabolism have highlighted the significance of specialized metabolites in the regulation of gene expression associated with biosynthetic networks. This opinion article focuses on the molecular mechanisms of small-molecule-mediated feedback regulation at the transcriptional level and its potential modes of action, including metabolite signal perception, the nature of the sensor, and the signaling transduction mechanisms leading to transcriptional and post-transcriptional regulation, based on evidence available from plants and other kingdoms of life. We also discuss the challenges associated with identifying the occurrences, effects, and localization of small molecule–protein interactions. Further understanding of small-molecule-controlled metabolic fluxes will enable rational design of transcriptional regulation systems in metabolic engineering to produce high-value specialized metabolites. [ABSTRACT FROM AUTHOR]

• Multi-omics analysis of effect of Subolesin knockdown on the regulome of tick cells. • Results support a key role for Subolesin in the tick cell regulome. • Differential proteins provide insights into vaccine protective mechanisms. • Differential proteins suggest candidate tick protective antigens. Ticks as obligate blood-feeding arthropod vectors of pathogenic viruses, bacteria, protozoa and helminths associated with prevalent tick-borne diseases (TBDs) worldwide. These arthropods constitute the second vector after mosquitoes that transmit pathogens to humans and the first vector in domestic animals. Vaccines constitute the safest and more effective approach to control tick infestations and TBDs, but research is needed to identify new antigens and improve vaccine formulations. The tick protein Subolesin (Sub) is a well-known vaccine protective antigen with a highly conserved sequence at both gene and protein levels in the Ixodidae and among arthropods and vertebrates. In this study, transcriptomics and proteomics analyses were conducted together with graph theory data analysis in wild type and Sub knockdown (KD) tick ISE6 cells in order to identify and characterize the functional implications of Sub in tick cells. The results support a key role for Sub in the regulation of gene expression in ticks and the relevance of this antigen in vaccine development against ticks and TBDs. Proteins with differential representation in response to Sub KD provide insights into vaccine protective mechanisms and candidate tick protective antigens. [ABSTRACT FROM AUTHOR]

• Stigma developmental stages revealed a bi-phase carotenoid biosynthetic pathway. While the synthesis of Lycopene peaks at S2 stage, β- carotene and apocarotenoids peaks at S3 and S4 stages, respectively. • CsPSY2, CsBCH and CsCCD2 genes play a pivotal role in apocarotenoid accumulation. • A gene complex (CsPIF1, CsHY5, CsPSY2) regulates stigma carotenoid biosynthesis. • The results indicate plastid development to S 1 & S 2 stigmas and chromoplast differentiation to S 3 and S 4 stigma stages. ORa gene correlates strongly with chromoplast biogenesis in stigmas. • Based on correlation networking, CsPIF1, CsHY5, and CsPSY2 likely form a complex to regulate carotenoid biosynthesis in stigmas. Integration of the apocarotenoid and transcriptome profiles in developing stigmas of saffron revealed a biphasic pattern of carotenoid biosynthetic pathway. While the synthesis of lycopene peaks at S 2 stage that of β- carotene and Cs LCY-β, peaks at S 3 stage of stigma development. Cs ZCD, Cs GTF, Cs BGSD, Cs ADH and Cs VDE, responsible for the oxidative cleavage of carotenoids to produce apocarotenoids, showed highest expression in S 4 stage stigmas. Cs PSY2, Cs BCH and Cs CCD2 showed the highest correlation with apocarotenoid accumulation in the stigmas, indicating them to be the key genes in carotenoid biosynthesis. Our results indicate active plastid development in yellow and orange stigmas and active chromoplast differentiation in red (S 3) and scarlet (S 4) stigmas. The expression of the OR-a gene in the stigmas was found to be strongly related to chromoplast biogenesis. On the basis of correlation networking, we suggest the involvement of a repression-activation transcriptional complex comprised of the Cs PIF1, Cs HY5 and Cs PSY2 genes in regulating the biosynthesis of carotenoids in the saffron stigmas. [ABSTRACT FROM AUTHOR]

Although the defining events of meiosis are highly conserved, such as genetic recombination and ploidy reduction, the regulation of meiotic entry and divisions is distinct between species and sexes. In mammals, the complex cellular milieu dictates the developmental timing and duration of meiosis and hinges on complex signaling from somatic cells. The unique and dramatic chromosomal events of meiosis and gametogenesis require diverse mechanisms of regulation of gene expression and cell cycle progression. The functional study of meiotic regulatory elements in animals is markedly hampered by the inability to efficiently recapitulate the entire process in cell culture paradigms. However, increasingly powerful genomic analyses are illuminating key aspects of meiotic gene expression such as transcription control, transcriptome epigenetics, and post-transcriptional regulation. Meiosis is essential for gamete production in all sexually reproducing organisms. It entails two successive cell divisions without DNA replication, producing haploid cells from diploid ones. This process involves complex morphological and molecular differentiation that varies across species and between sexes. Specialized genomic events like meiotic recombination and chromosome segregation are tightly regulated, including preparation for post-meiotic development. Research in model organisms, notably yeast, has shed light on the genetic and molecular aspects of meiosis and its regulation. Although mammalian meiosis research faces challenges, particularly in replicating gametogenesis in vitro , advances in genetic and genomic technologies are providing mechanistic insights. Here we review the genetics and molecular biology of meiotic gene expression control, focusing on mammals. [ABSTRACT FROM AUTHOR]

Gene transcription patterns can be perturbed by modulating epigenetic marks using photoresponsive probes. Photoswitches and photocages offer unprecedented precision in studying (RNA) epigenetics from in vitro to downstream events in vivo. RNA epigenetics is in its infancy, but provides a new multi-layer code where precise intervention may contribute to its deciphering. Optochemical tools have become potent instruments for understanding biological processes at the molecular level, and the past decade has witnessed their use in epigenetics and epitranscriptomics (also known as RNA epigenetics) for deciphering gene expression regulation. By using photoresponsive molecules such as photoswitches and photocages, researchers can achieve precise control over when and where specific events occur. Therefore, these are invaluable for studying both histone and nucleotide modifications and exploring disease-related mechanisms. We systematically report and assess current examples in the field, and identify open challenges and future directions. These outstanding proof-of-concept investigations will inspire other chemical biologists to participate in these emerging fields given the potential of photochromic molecules in research and biomedicine. [ABSTRACT FROM AUTHOR]

Our new structure-based classification provides a more comprehensive/systematic understanding of bacterial transcriptional activation utilizing categorization based on the transcription factor (TF)/DNA/RNA polymerase (RNAP) interactions involved. The majority of transcription factors (TFs) bind to the upstream sites of the –35 element but differ in interaction with RNAP/DNA. Such differences often play a crucial role and could define important aspects of the molecular mechanism of transcription activation. Certain TFs bind to the promoter spacer region to enhance promoter recognition and activate transcription via DNA topology modification or adaptation of RNAP with remodeling or bridging interactions. Notably, numerous TFs interact only with RNAP rather than with the promoter DNA to activate transcription. Transcription activation is an important checkpoint of regulation of gene expression which occurs in response to different intracellular and extracellular signals. The key elements in this signal transduction process are transcription activators, which determine when and how gene expression is activated. Recent structural studies on a considerable number of new transcription activation complexes (TACs) revealed the remarkable mechanistic diversity of transcription activation mediated by different factors, necessitating a review and re-evaluation of the transcription activation mechanisms. In this review, we present a comprehensive summary of transcription activation mechanisms and propose a new, elaborate, and systematic classification of transcription activation mechanisms, primarily based on the structural features of diverse TAC components. [ABSTRACT FROM AUTHOR]

Histone 2A monoubiquitination (uH2A) underscores a key epigenetic regulation of gene expression. In this report, we show that the deubiquitinase for uH2A, ubiquitin-specific peptidase 16 (USP16), is modified by O-linked N-acetylglucosamine (OGlcNAc). O-GlcNAcylation involves the installation of the OGlcNAc moiety to Ser/Thr residues. It crosstalks with Ser/Thr phosphorylation, affects protein--protein interaction, alters enzyme activity or protein folding, and changes protein subcellular localization. In our study, we first confirmed that USP16 is glycosylated on Thr203 and Ser214, as reported in a previous chemoenzymatic screen. We then discovered that mutation of the O-GlcNAcylation site Thr203, which is adjacent to deubiquitination-required Cys204, reduces the deubiquitination activity toward H2AK119ub in vitro and in cells, while mutation on Ser214 had the opposite effects. Using USP16 Ser552 phosphorylation-specific antibodies, we demonstrated that O-GlcNAcylation antagonizes cyclin-dependent kinase 1--mediated phosphorylation and promotes USP16 nuclear export. O-GlcNAcylation of USP16 is also required for deubiquitination of Polo-like kinase 1, a mitotic master kinase, and the subsequent chromosome segregation and cytokinesis. In summary, our study revealed that O-GlcNAcylation of USP16 at Thr203 and Ser214 coordinates deubiquitination of uH2A and Polo-like kinase 1, thus ensuring proper cell cycle progression. [ABSTRACT FROM AUTHOR]

Inositol phosphates and their metabolites play a significant role in several biochemical pathways, gene expression regulation, and phosphate homeostasis. Among the different inositol phosphates, inositol hexakisphosphate (IP6) is a substrate of inositol hexakisphosphate kinases (IP6Ks), which phosphorylate one or more of the IP6 phosphate groups. Pyrophosphorylation of IP6 leads to the formation of inositol pyrophosphates, high-energy signaling molecules that mediate physiological processes through their ability to modify target protein activities, either by directly binding to their target protein or by pyrophosphorylating protein serine residues. 5-diphosphoinositol pentakisphosphate, the most abundant inositol pyrophosphate in mammals, has been extensively studied and found to be significantly involved in a wide range of physiological processes. Three IP6K (IP6K1, IP6K2, and IP6K3) isoforms regulate IP7 synthesis in mammals. Here, we summarize our current understanding of IP6K1's roles in cytoskeletal remodeling, trafficking, cellular migration, metabolism, gene expression, DNA repair, and immunity. We also briefly discuss current gaps in knowledge, highlighting the need for further investigation. [ABSTRACT FROM AUTHOR]

Discovery of impacts of RNA modifications in liver disease has accelerated recently, with research on N6-methyladenosine and 5-methylcytosine proving particularly fruitful. These findings have yielded potential biomarkers and therapeutics to inform prognosis and course of treatment for hepatocellular carcinoma and metabolic-associated steatohepatitis, and are likely to continue to yield results for other liver diseases. Despite these advances, a full mechanistic understanding of RNA modifications has been slow to advance owing to experimental limitations and the outsized impact of low levels of RNA modification. Both mechanistic studies looking at specific RNA modification sites and broad multi-omic studies using patient samples should be continued, with each type of study potentially informing the other and leading to novel insights into mechanisms and alternative effects of RNA-modifying enzymes and RNA modifications. RNA modifications have emerged as important mechanisms of gene regulation. Developmental, metabolic, and cell cycle regulatory processes are all affected by epitranscriptomic modifications, which control gene expression in a dynamic manner. The hepatic tissue is highly metabolically active and has an impressive ability to regenerate after injury. Cell proliferation, differentiation, and metabolism, which are all essential to the liver response to injury and regeneration, are regulated via RNA modification. Two such modifications, N 6-methyladenosine (m6A)and 5-methylcytosine (m5C), have been identified as prognostic disease markers and potential therapeutic targets for liver diseases. Here, we describe progress in understanding the role of RNA modifications in liver biology and disease and discuss specific areas where unexpected results could lead to improved future understanding. RNA modifications have emerged as important mechanisms of gene regulation. Developmental, metabolic, and cell cycle regulatory processes are all affected by epitranscriptomic modifications, which control gene expression in a dynamic manner. The hepatic tissue is highly metabolically active and has an impressive ability to regenerate after injury. Cell proliferation, differentiation, and metabolism, which are all essential to the liver response to injury and regeneration, are regulated via RNA modification. Two such modifications, N 6-methyladenosine (m6A)and 5-methylcytosine (m5C), have been identified as prognostic disease markers and potential therapeutic targets for liver diseases. Here, we describe progress in understanding the role of RNA modifications in liver biology and disease and discuss specific areas where unexpected results could lead to improved future understanding. [ABSTRACT FROM AUTHOR]

Macrophage senescence, manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype, has long been considered harmful. Persistent senescence of macrophages may lead to maladaptation, immune dysfunction, and finally the development of age-related diseases, infections, autoimmune diseases, and malignancies. However, it is a ubiquitous, multi-factorial, and dynamic complex phenomenon that also plays roles in remodeled processes, including wound repair and embryogenesis. In this review, we summarize some general molecular changes and several specific biomarkers during macrophage senescence, which may bring new sight to recognize senescent macrophages in different conditions. Also, we take an in-depth look at the functional changes in senescent macrophages, including metabolism, autophagy, polarization, phagocytosis, antigen presentation, and infiltration or recruitment. Furthermore, some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated, not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential targets or drugs clinically. Senescent macrophages are characterized by specific molecular and functional changes, leading to tissue degenerations and diseases. Targeting macrophage senescence is expected to be a novel strategy for disease intervention. [Display omitted] [ABSTRACT FROM AUTHOR]

The study aimed to observe molecular signaling, including reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm), to evaluate the alteration of gene expression by low-level laser therapy (LLLT) and the correlation between its mechanisms and the NF-kB pathway in cells involved in orthodontic tooth movement. Osteoblast-like cells (MG63), immortalized periodontal ligament cells (iPDL), and M1 macrophage-like cells were irradiated by 980-nm LLLT with energy densities of 1 and 10 J/cm2 ΔΨm and intracellular ROS were monitored using fluorescent probes. The changes of mRNA expression were assessed using reverse transcription polymerase chain reaction (RT-PCR). NF-kB inhibitor, ROS scavenger, and ΔΨm suppressor were used to analyze signals associated with the regulation of gene expression. Finally, Western blot analysis was performed to confirm NF-kB signaling after LLLT. We found the increases of ΔΨm and ROS in all three cell types after LLLT, but no significant difference was observed between 1 and 10 J/cm2 LLLT. Regarding gene expression, some target genes were upregulated in MG63 6 h, 12 h, and 1 day after LLLT and in iPDL cells 12 h and 1 day after LLLT. However, no changes occurred in M1 cells. The inhibitor that significantly reduced most changes in gene expression was NF-kB inhibitor. Western blot analysis showed the increase in p-IkBα level after LLLT in iPDL and MG63, but not in M1. The 980-nm LLLT increased ΔΨm and ROS production in all three cell types. However, changes in gene regulation were found only in MG63 and iPDL cells, which related to the NF-kB pathway. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and is associated with a range of adverse clinical outcomes. Accumulating evidence points to inflammatory processes resulting from innate immune responses as a cornerstone in AF pathogenesis. Genetic and epigenetic factors affecting leukocytes have been identified as key modulators of the inflammatory response. Inherited variants in genes encoding proteins involved in the innate immune response have been associated with increased risk for AF recurrence and stroke in AF patients. Furthermore, acquired somatic mutations associated with clonal hematopoiesis of indeterminate potential, leukocyte telomere shortening, and epigenetic age acceleration contribute to increased AF risk. In individuals carrying clonal hematopoiesis of indeterminate potential, myocardial monocyte-derived macrophage shift toward a proinflammatory phenotype may precipitate AF. Further studies are needed to better understand the role of genetic regulation of the native immune response in atrial arrhythmogenesis and its therapeutic potential as a target for personalized medicine. [Display omitted] • Inflammation plays a fundamental role in the pathogenesis of AF. • Genetic and epigenetic factors modulate inflammatory responses, and genetic variants influence the risk of developing AF. • Better understanding of the role of genetic variants affecting AF could enhance identification and individualized management of patients at risk. [ABSTRACT FROM AUTHOR]