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Dysregulation of the oncogenic transcription factor HOXA9 is a prominent feature for most aggressive acute myeloid leukemia cases and a strong indicator of poor prognosis in patients. Leukemia subtypes with hallmark overexpression of HOXA9 include those carrying MLL gene rearrangements, NPM1c mutations, and other genetic alternations. A growing body of evidence indicates that HOXA9 dysregulation is both sufficient and necessary for leukemic transformation. The HOXA9 mRNA and protein regulation includes multi-layered controls by transcription factors (such as CDX2/4 and USF2/1), epigenetic factors (such as MLL-Menin-LEDGF, DOT1L, ENL, HBO1, NPM1c-XPO1, and polycomb proteins), microRNAs (such as miR-126 and miR-196b), long non-coding RNAs (such as HOTTIP), three-dimensional chromatin interactions, and post-translational protein modifications. Recently, insights into the dynamic regulation of HOXA9 have led to an advanced understanding of the HOXA9 regulome and provided new cancer therapeutic opportunities, including developing inhibitors targeting DOT1L, Menin, and ENL proteins. This review summarizes recent advances in understanding the molecular mechanisms controlling HOXA9 regulation and the pharmacological approaches that target HOXA9 regulators to treat HOXA9-driven acute myeloid leukemia.

Understanding how epigenetic variation in non-coding regions is involved in distal gene-expression regulation is an important problem. Regulatory regions can be associated to genes using large-scale datasets of epigenetic and expression data. However, for regions of complex epigenomic signals and enhancers that regulate many genes, it is difficult to understand these associations. We present StitchIt, an approach to dissect epigenetic variation in a gene-specific manner for the detection of regulatory elements (REMs) without relying on peak calls in individual samples. StitchIt segments epigenetic signal tracks over many samples to generate the location and the target genes of a REM simultaneously. We show that this approach leads to a more accurate and refined REM detection compared to standard methods even on heterogeneous datasets, which are challenging to model. Also, StitchIt REMs are highly enriched in experimentally determined chromatin interactions and expression quantitative trait loci. We validated several newly predicted REMs using CRISPR-Cas9 experiments, thereby demonstrating the reliability of StitchIt. StitchIt is able to dissect regulation in superenhancers and predicts thousands of putative REMs that go unnoticed using peak-based approaches suggesting that a large part of the regulome might be uncharted water.

Eosinophils develop in the bone marrow from hematopoietic progenitors into mature cells capable of a plethora of immunomodulatory roles via the choreographed process of eosinophilopoiesis. However, the gene regulatory elements and transcription factors (TFs) orchestrating this process remain largely unknown. The potency and resulting diversity fundamental to an eosinophil’s complex immunomodulatory functions and tissue specialization likely result from dynamic epigenetic regulation of the eosinophil genome, a dynamic eosinophil regulome. In this study, we applied a global approach using broad-range, next-generation sequencing to identify a repertoire of eosinophil-specific enhancers. We identified over 8200 active enhancers located within 1–20 kB of expressed eosinophil genes. TF binding motif analysis revealed PU.1 (Spi1) motif enrichment in eosinophil enhancers, and chromatin immunoprecipitation coupled with massively parallel sequencing confirmed PU.1 binding in likely enhancers of genes highly expressed in eosinophils. A substantial proportion (>25%) of these PU.1-bound enhancers were unique to murine, culture-derived eosinophils when compared among enhancers of highly expressed genes of three closely related myeloid cell subsets (macrophages, neutrophils, and immature granulocytes). Gene ontology analysis of eosinophil-specific, PU.1-bound enhancers revealed enrichment for genes involved in migration, proliferation, degranulation, and survival. Furthermore, eosinophil-specific superenhancers were enriched in genes whose homologs are associated with risk loci for eosinophilia and allergic diseases. Our collective data identify eosinophil-specific enhancers regulating key eosinophil genes through epigenetic mechanisms (H3K27 acetylation) and TF binding (PU.1).

To investigate cross-ancestry genetics of complex traits, we conducted a phenome-wide analysis of loci with heterogeneous effects across African, Admixed-American, Central/South Asian, East Asian, European and Middle Eastern participants of the UK Biobank (N = 441 331). Testing 843 phenotypes, we identified 82 independent genomic regions mapping variants showing genome-wide significant (GWS) associations (P

Macrophages are ubiquitous custodians of tissues, which play decisive role in maintaining cellular homeostasis through regulatory immune responses. Within tissues, macrophage exhibit extremely heterogeneous population with varying functions orchestrated through regulatory response, which can be further exacerbated in diverse genetic backgrounds. Gene regulatory networks (GRNs) offer comprehensive understanding of cellular regulatory behavior by unfolding the transcription factors (TFs) and regulated target genes. RNA-Seq coupled with ATAC-Seq has revolutionized the regulome landscape influenced by gene expression modeling. Here, we employ an integrative multi-omics systems biology-based analysis and generated GRNs derived from the unstimulated bone marrow-derived macrophages of five inbred genetically defined murine strains, which are reported to be linked with most of the population-wide human genetic variants. Our probabilistic modeling of a basal hemostasis pan regulatory repertoire in diverse macrophages discovered 96 TFs targeting 6279 genes representing 468,291 interactions across five inbred murine strains. Subsequently, we identify core and distinctive GRN sub-networks in unstimulated macrophages to describe the system-wide conservation and dissimilarities, respectively across five murine strains. Our study concludes that discrepancies in unstimulated macrophage-specific regulatory networks not only drives the basal functional plasticity within genetic backgrounds, additionally aid in understanding the complexity of racial disparity among the human population during stress.

Neuronal activity-dependent gene expression is essential for brain development. Although transcriptional and epigenetic effects of neuronal activity have been explored in mice, such an investigation is lacking in humans. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible after membrane depolarization, some of which have specifically evolved in primates and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk. Boulting et al. profile activity-dependent gene expression and regulatory elements in human induced pluripotent stem cell-derived GABAergic neurons and uncover a possible role for calcium-responsive gene promoters of these neurons in autism risk.

Cellular metabolism regulates immune cell activation, differentiation and effector functions, but current metabolic approaches lack single-cell resolution and simultaneous characterization of cellular phenotype. In this study, we developed an approach to characterize the metabolic regulome of single cells together with their phenotypic identity. The method, termed single-cell metabolic regulome profiling (scMEP), quantifies proteins that regulate metabolic pathway activity using high-dimensional antibody-based technologies. We employed mass cytometry (cytometry by time of flight, CyTOF) to benchmark scMEP against bulk metabolic assays by reconstructing the metabolic remodeling of in vitro-activated naive and memory CD8+ T cells. We applied the approach to clinical samples and identified tissue-restricted, metabolically repressed cytotoxic T cells in human colorectal carcinoma. Combining our method with multiplexed ion beam imaging by time of flight (MIBI-TOF), we uncovered the spatial organization of metabolic programs in human tissues, which indicated exclusion of metabolically repressed immune cells from the tumor–immune boundary. Overall, our approach enables robust approximation of metabolic and functional states in individual cells.

Doxorubicin is an efficient chemotherapeutic reagent in the treatment of a variety of cancers. However, its underlying molecular mechanism is not fully understood and several severe side effects limit its application. In this study, the dynamic transcriptomic response of Saccharomyces cerevisiae cells to a doxorubicin pulse in a chemostat system was investigated to reveal the underlying molecular mechanism of this drug. The clustering of differentially and significantly expressed genes (DEGs) indicated that the response of yeast cells to doxorubicin is time dependent and may be classified as short-term, mid-term and long-term responses. The cells have started to reorganize their response after the first minute following the injection of the pulse. A modified version of Weighted Gene Co-expression Network Analysis (WGCNA) was used to cluster the positively correlated co-expression profiles, and functional enrichment analysis of these clusters was carried out. DNA replication and DNA repair processes were significantly affected and induced 60 minutes after exposure to doxorubicin. The response to oxidative stress was not identified as a significant term. A transcriptional re-organization of the metabolic pathways seems to be an early event and persists afterwards. The present study reveals for the first time that the RNA surveillance pathway, which is a post-transcriptional regulatory pathway, may be implicated in the short-term reaction of yeast cells to doxorubicin. Integration with regulome revealed the dynamic re-organization of the transcriptomic landscape. Fhl1p, Mbp1p, and Mcm1p were identified as primary regulatory factors responsible for tuning the differentially expressed genes.

Colorectal cancer (CRC) is one of the most malignant cancers and results in a substantial rate of morbidity and mortality. Diagnosis of this malignancy in early stages increases the chance of effective treatment. High-throughput data analyses reveal omics signatures and also provide the possibility of developing computational models for early detection of this disease. Such models would be able to use as complementary tools for early detection of different types of cancers including CRC. In this study, using gene expression data, the Flux balance analysis (FBA) applied to decode metabolic fluxes in cancer and normal cells. Moreover, transcriptome and genome analyses revealed driver agents of CRC in a biological network scheme. By applying comprehensive publicly available data from TCGA, different aspect of CRC regulome including the regulatory effect of gene expression, methylation, microRNA, copy number aberration and point mutation profile over protein levels investigated and the results provide a regulatory picture underlying CRC. Compiling omics profiles indicated snapshots of changes in different omics levels and flux rate of CRC. In conclusion, considering obtained CRC signatures and their role in biological operating systems of cells, the results suggest reliable driver regulatory modules that could potentially serve as biomarkers and therapeutic targets and furthermore expand our understanding of driving mechanisms of this disease.br /.

Aim: To investigate the associations between single nucleotide polymorphisms (SNPs) in miRNA regulome and nonsyndromic orofacial clefts. Materials & methods: The associations were evaluated by logistic regression model in stage I (504 cases and 455 controls) and stage II (1500 cases and 1386 controls). Functional experiments including luciferase activity assay, cell apoptosis and proliferation, serum miRNA expression, and mouse embryo RNA sequencing were performed. Results: Rs3830766 in the enhancer of hsa-miR-4260 was associated with cleft lip only (CLO) and enhancer activity. Hsa-miR-4260 expression decreased in the serum of CLO. Overexpression of miR-4260 inhibited cell proliferation and promoted cell apoptosis. UBB was the target gene of hsa-miR-4260. Conclusion: Rs3830766 in the hsa-miR-4260 enhancer that can interact with UBB was relevant to CLO.

The development of sequencing technologies has promoted the survey of genome-wide chromatin accessibility at single-cell resolution. However, comprehensive analysis of single-cell epigenomic profiles remains a challenge. Here, we introduce an accessibility pattern-based epigenomic clustering (APEC) method, which classifies each cell by groups of accessible regions with synergistic signal patterns termed “accessons”. This python-based package greatly improves the accuracy of unsupervised single-cell clustering for many public datasets. It also predicts gene expression, identifies enriched motifs, discovers super-enhancers, and projects pseudotime trajectories. APEC is available at https://github.com/QuKunLab/APEC.

The transcription factor IRF8 (ICSBP) is required for the development and maturation of myeloid cells (dendritic cells, monocytes, macrophages), and for expression of intrinsic anti-microbial function such as antigen capture, processing and presentation to lymphoid cells, and for activation of these cells in response to cytokines and pro-inflammatory stimuli (IFN-γ, IFN-β, LPS). IRF8 deficiency in humans causes a severe primary immunodeficiency presenting as susceptibility to infections, complete or severe depletion of blood dendritic cells (DC) subsets, depletion of CD14+ and CD16+ monocytes and reduced numbers and impaired activity of NK cells. In genome-wide association studies (GWAS), sequence variants near IRF8 are significant risk factors for multiple chronic inflammatory diseases in humans including inflammatory bowel disease, lupus, rheumatoid arthritis, multiple sclerosis, and several others. Recent studies have cataloged all the genes bound by and transcriptionally activated by IRF8 in myeloid cells, either alone or in combination with other transcription factors (PU.1, IRF1, STAT1) at steady state and in response to pro-inflammatory stimuli. This IRF1/IRF8 regulome comprises immune pathways such as antigen processing and presentation pathways, expression of costimulatory molecules, cytokines and chemokines, response to stimuli such as cytokine receptors, pathogen-associated molecular pattern receptors, TLRs and nucleotide-binding oligomerization domain-like receptor signaling pathways, and small antiviral GTPases. Members of the IRF8/IRF1 regulome are over-represented amongst genes in which mutations cause primary immunodeficiencies, and are specifically enriched at GWAS loci associated with chronic inflammatory diseases in humans. These recent studies highlight a critical role of IRF8 in the activity of several immune cell types for protection against infections, but also in pathological inflammation associated with common human inflammatory conditions.

Objective The TLR3/cGAS‐STING‐IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Methods The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. Results Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11‐2.53, P‐value = .01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07‐3.84, P‐value = .03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03‐2.27, P‐value = .03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5‐6 risk alleles compared to those with 0‐2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair‐wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. Conclusions Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management., Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.

Cancer incidence is rapidly growing, and cancer is the leading cause of death worldwide in the 21st century. Hepatocyte nuclear factor 1B (HNF1B) is a transcription factor that involves the growth and development of multiple organs. The aim of this study was to explore the significance of HNF1B in human cancer by an integrative analysis of online databases. The UALCAN database, cBio cancer genomics portal, Cancer Regulome tools, Kaplan-Meier plotter and Tumor IMmune Estimation Resource (TIMER) website were used to perform the corresponding analysis. The results showed that HNF1B is dysregulated in various cancers and associated with the differential overall survival of cancer patients. HNF1B showed many mutation forms and high mutation levels in different cancer types. In addition, we found that HNF1B interacted with different genes in multiple aspects. Moreover, HNF1B expression is associated with many immune cell infiltration levels and influences the prognostic prediction of immune cells in some kinds of cancers. In conclusion, HNF1B plays a significant role in cancer and may be a potential target for cancer immunotherapy.

Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in the transcriptome and develop de novo multi-drug resistance. As a critical component in transcriptional regulation, how the chromatin landscape is transformed in MM cells exposed to BMSCs and contributes to the transcriptional response to BMSCs remains elusive. We profiled the transcriptome and regulome for MM cells using a transwell coculture system with BMSCs. The transcriptome and regulome of MM cells from the upper transwell resembled MM cells that coexisted with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in the JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with increasing accessibility at multiple regulatory sites were preferentially induced by BMSCs; these genes were enriched in functions linked to responses to drugs and unfavorable clinic outcomes. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulate the BMSC-induced transformation of the regulome linked to the transcriptional response. Together, we characterized the BMSC-induced transcriptome and regulome signatures of MM cells to facilitate research on epigenetic mechanisms of BMSC-induced multi-drug resistance in MM.

Vaccines are the most effective preventive intervention to reduce the impact of infectious diseases worldwide. In particular, tick-borne diseases represent a growing burden for human and animal health worldwide and vaccines are the most effective and environmentally sound approach for the control of vector infestations and pathogen transmission. However, the development of effective vaccines for the control of tick-borne diseases with combined vector-derived and pathogen-derived antigens is one of the limitations for the development of effective vaccine formulations. Quantum biology arise from findings suggesting that living cells operate under non-trivial features of quantum mechanics, which has been proposed to be involved in DNA mutation biological process. Then, the electronic structure of the molecular interactions behind peptide immunogenicity led to quantum immunology and based on the definition of the photon as a quantum of light, the immune protective epitopes were proposed as the immunological quantum. Recently, a quantum vaccinomics approach was proposed based on the characterization of the immunological quantum to further advance the design of more effective and safe vaccines. In this chapter, we describe methods of the quantum vaccinomics approach based on proteins with key functions in cell interactome and regulome of vector–host–pathogen interactions for the identification by yeast two-hybrid screen and the characterization by in vitro protein–protein interactions and musical scores of protein interacting domains, and the characterization of conserved protective epitopes in protein interacting domains. These results can then be used for the design and production of chimeric protective antigens., This work was supported by the Ministerio de Economía, Industria y Competitividad (Spain) grant BFU2016-79892-P. Marinela Contreras is funded by the Ministerio de Ciencia, Innovación y Universidades, Spain, grant FJC-2018-038277-I. Sara Artigas-Jerónimo is supported by a predoctoral fellowship by the University of Castilla-La Mancha, UCLM, Spain.

Cis-regulomes underlying immune-cell-specific genomic states have been extensively analyzed by structure-based chromatin profiling. By coupling such approaches with a high-throughput enhancer screen (self-transcribing active regulatory region sequencing (STARR–seq)), we assembled a functional cis-regulome for lipopolysaccharide-activated B cells. Functional enhancers, in contrast with accessible chromatin regions that lack enhancer activity, were enriched for enhancer RNAs (eRNAs) and preferentially interacted in vivo with B cell lineage-determining transcription factors. Interestingly, preferential combinatorial binding by these transcription factors was not associated with differential enrichment of their sites. Instead, active enhancers were resolved by principal component analysis (PCA) from all accessible regions by co-varying transcription factor motif scores involving a distinct set of signaling-induced transcription factors. High-resolution chromosome conformation capture (Hi-C) analysis revealed multiplex, activated enhancer–promoter configurations encompassing numerous multi-enhancer genes and multi-genic enhancers engaged in the control of divergent molecular pathways. Motif analysis of pathway-specific enhancers provides a catalog of diverse transcription factor codes for biological processes encompassing B cell activation, cycling and differentiation. Singh and colleagues leverage genome-wide assays to identify functionally active enhancers that are present in naive and lipopolysaccharide-activated B cells by FAIRE–seq, STARR–seq and Hi-C structural interactome analyses and identify additional transcription factors that regulate gene expression modules.

A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, identifying major age-related alterations in hepatic gene expression may pinpoint ontogenetic shifts with important hepatic and systemic consequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of individual decline. Next-generation sequencing (NGS) data analyzed by the Mann–Whitney nonparametric test and Ensemble Feature Selection (EFS) bioinformatics identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly (p = 0.0003 to 0.0464) and strikingly (EFS score > 0.3:16 transcripts; EFS score > 0.2:28 transcripts) differ between young and old livers. Most of these age-related transcripts were assigned to the categories ‘regulome’, ‘inflammaging’, ‘regeneration’, and ‘pharmacogenes’. NGS results were confirmed by quantitative real-time polymerase chain reaction. Our results have important implications for the areas of ontogeny/aging and the age-dependent increase in major liver diseases. Finally, we present a broadly substantiated and testable hypothesis on a genetically governed ‘aging cascade’, wherein PPP1R10 acts as a putative ontogenetic master regulator, prominently flanked by IGFALS and DUSP1. This transcriptome-wide analysis of human liver offers potential clues towards developing safer and improved therapeutic interventions against major liver diseases and increased insights into key mechanisms underlying aging.

Ticks and tick-borne pathogens such as Anaplasma phagocytophilum affect human and animal health worldwide and thus the characterization of host/tick–pathogen interactions is important for the control of tick-borne diseases. The vertebrate regulatory proteins Akirins and its tick ortholog, Subolesin, are conserved throughout the metazoan and involved in the regulation of different biological processes such as immune response to pathogen infection. Akirin/Subolesin have a key role in host/tick–pathogen interactions and exert its regulatory function primarily through interacting proteins such as transcription factors, chromatin remodelers and RNA-associated proteins. Recent results have provided evidence of akirin/subolesin genetic interactions and the interaction of Akirin/Subolesin with histones, thus suggesting a role in direct chromatin remodeling. Finally, and still to be proven, some models suggest the possibility of direct Akirin/Subolesin protein interactions with DNA. Future research should advance the characterization of Akirin/Subolesin interactome and its functional role at the host/tick–pathogen interface. These results have implications for translational biotechnology and medicine for the development of new effective interventions for the control of ticks and tick-borne diseases., This research was financially supported by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033), Spain and by ERDF A way of making Europe grant BFU2016-79892-P and CSIC-IREC grant 2020AEP123. SA-J was supported by a predoctoral fellowship of the UCLM.

Despite the involvement of Poly(ADP-ribose) polymerase-1 (PARP1) in many important biological pathways, the target residues of PARP1-mediated ADP-ribosylation remain ambiguous. To explicate the ADP-ribosylation regulome, we analyze human cells depleted for key regulators of PARP1 activity, histone PARylation factor 1 (HPF1) and ADP-ribosylhydrolase 3 (ARH3). Using quantitative proteomics, we characterize 1,596 ADP-ribosylation sites, displaying up to 1000-fold regulation across the investigated knockout cells. We find that HPF1 and ARH3 inversely and homogenously regulate the serine ADP-ribosylome on a proteome-wide scale with consistent adherence to lysine-serine-motifs, suggesting that targeting is independent of HPF1 and ARH3. Notably, we do not detect an HPF1-dependent target residue switch from serine to glutamate/aspartate under the investigated conditions. Our data support the notion that serine ADP-ribosylation mainly exists as mono-ADP-ribosylation in cells, and reveal a remarkable degree of histone co-modification with serine ADP-ribosylation and other post-translational modifications., ADP-ribosylation is regulated by HPF1 and ARH3, but the cellular target spectrum of these enzymes is not fully understood. Here, the authors use quantitative proteomics to define the HPF1- and ARH3-dependent ADP-ribosylome, providing evidence that mono-ADP-ribosylation of serine predominates in cells.

Microglia are brain resident myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimer’s Disease (AD). Yet our understanding of how the genetic regulatory landscape controls microglial function and contributes to disease is limited. Here, we performed transcriptome and chromatin accessibility profiling in primary human microglia from 150 donors to identify genetically-driven variation and cell-specific enhancer-promoter interactions. Integrative fine-mapping analysis identified putative regulatory mechanisms for 21 AD risk loci, of which 18 were refined to a single gene, including 3 novel genes (KCNN4, FIBP and LRRC25). Transcription factor regulatory networks captured AD risk variation and identified SPI1 as a key regulator of microglia expression and AD risk. This comprehensive resource capturing variation in the human microglia regulome provides novel insights into the etiology of neurodegenerative disease.One-Sentence SummaryCharacterizing the genetic regulation of chromatin accessibility and gene expression in human microglia refines molecular mechanisms of Alzheimer’s disease risk loci.

In this work, we used Nanostring N-counter technology, to evaluate the mRNA expression level of more than 330 regulatory genes over 34-time points covering the first three days of development of the sea urchin larvae. The hierarchical clustering of the mRNAs expression levels has identified groups corresponding to the major developmental landmarks (e.g., maternal to zygotic transition and gastrulation). Furthermore, comparison with previous experiments indicates high reproducibility of mRNA level temporal dynamics across batches. Finally, we generated an online tool to visualize gene expression during sea urchin larval development. The site can be accessed at https://nanostring2021.herokuapp.com/.

Aim To reveal the molecular mechanism of anti-angiogenic activity of semisynthetic triterpenoid CDDO-Im. Materials and methods Using re-analysis of cDNA microarray data of CDDO-Im-treated human vascular endothelial cells (HUVECs) (GSE71622), functional annotation of revealed differentially expressed genes (DEGs) and analysis of their co-expression, the key processes induced by CDDO-Im in HUVECs were identified. Venn diagram analysis was further performed to reveal the common DEGs, i.e. genes both susceptible to CDDO-Im and involved in the regulation of angiogenesis. A list of probable protein targets of CDDO-Im was prepared based on Connectivity Map/cheminformatics analysis and chemical proteomics data, among which the proteins that were most associated with the angiogenesis-related regulome were identified. Finally, identified targets were validated by molecular docking and text mining approaches. Key findings The effect of CDDO-Im in HUVECs can be divided into two main phases: the short early phase (0.5–3 h) with an acute FOXD1/CEBPA/JUNB-regulated pro-angiogenic response induced by xenobiotic stress, and the second anti-angiogenic step (6–24 h) with massive suppression of various angiogenesis-related processes, accompanied by the activation of cytoprotective mechanisms. Our analysis showed that the anti-angiogenic activity of CDDO-Im is mediated by its inhibition of the expression of PLAT, ETS1, A2M, SPAG9, RASGRP3, FBXO32, GCNT1 and HDGFRP3 and its direct interactions with EGFR, mTOR, NOS2, HSP90AA1, MDM2, SYK, IRF3, ATR and KIF14. Significance Our findings provide valuable insights into the understanding of the molecular mechanisms of the anti-angiogenic activity of cyano enone-bearing triterpenoids and revealed a range of novel promising therapeutic targets to control pathological neovascularization.

Background Ceramide plays an important role in the occurrence and development of tumor. The synthesis of ceramide needs the participation of LASS. Current studies have shown that different LASS family members play different functions in tumors, especially LASS6, has been proved to play a key role in breast cancer, gastric cancer, melanoma and so on, but the research on ovarian cancer is very limited. Methods Bioinformatics web resources, including Oncomine, UALCAN, Kaplan–Meier Plotter and TIMER were used to analyze the expression profile, prognostic value and immune infiltration of LASS6. The related genes of LASS6 in ovarian cancer were mined by Regulome Explorer and LinkedOmics database, and cluster analysis was done by DAVID. The PPI network involving LASS6 was constructed by STRING database. Finally, the correlation between 10 genes and LASS6 was analyzed by GEPIA database, and their prognostic value in ovarian cancer was analyzed by Kaplan–Meier plotter. Results The expression of LASS6 was up-regulated in ovarian cancer, which was related to the progression and poor prognosis of ovarian cancer. Through GO/KEGG cluster analysis, we also found that LASS6 may affect calcium ion channel and its transport pathways. The analysis of regulatory network involved in LASS6 showed that the high mRNAs of 7 key genes were associated with poor prognosis of OS in patients with ovarian cancer, among which DEGS1 was the most significant. Conclusions LASS6 may play an important role in the regulation of calcium pathway and become a new therapeutic target and potential prognostic marker in ovarian cancer.

Plant genomes encode a complex and evolutionary diverse regulatory grammar that forms the basis for most life on earth. A wealth of regulome and epigenome data have been generated in various plant species, but no common, standardized resource is available so far for biologists. Here we present ChIP-Hub, an integrative web-based platform in the ENCODE standards that bundles > 10000 publicly available datasets reanalyzed from > 40 plant species, allowing visualization and meta-analysis. We manually curate the datasets through assessing ~ 540 original publications and comprehensively evaluate their data quality. As a proof of concept, we extensively survey the co-association of different regulators and construct a hierarchical regulatory network under a broad developmental context. Furthermore, we show how our annotation allows to investigate the dynamic activity of tissue-specific regulatory elements (promoters and enhancers) and their underlying sequence grammar. Finally, we analyze the function and conservation of tissue-specific chromatin states based on comparative genomics. Taken together, the ChIP-Hub platform and the analysis results provide rich resources for deep exploration of plant ENCODE.

Prions are often considered as molecular memory devices, generating reproducible memory of a conformational change. Prion-like proteins (PrLPs) have been widely demonstrated to be present in plants, but their role in plant stress and memory remains unexplored. In this work, we report the widespread presence of PrLPs in plants through a comprehensive meta-analysis of 39 genomes representing major taxonomic groups. We find diverse functional roles associated with these proteins in various species and term the full complement of PrLPs in a genome as its “prionome.” In particular, we found the rice prionome being significantly enriched in transposons/retrotransposons (Ts/RTRs) and identified over 60 rice PrLPs that were differentially regulated in stress and developmental responses. This prompted us to explore whether and to what extent PrLPs may build stress memory. By integrating the available rice interactome, transcriptome, and regulome data sets, we could find links between stress and memory pathways that would not have otherwise been discernible. Regulatory inferences derived from the superimposition of these data sets revealed a complex network and cross talk between PrLPs, transcription factors (TFs), and the genes involved in stress priming. This integrative meta-analysis connects transient and transgenerational memory mechanisms in plants with PrLPs, suggesting that plant memory may rely upon protein-based signals in addition to chromatin-based epigenetic signals. Taken together, our work provides important insights into the anticipated role of prion-like candidates in stress and memory, paving the way for more focused studies for validating the role of the identified PrLPs in memory acclimation.