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Highlights: [•] Changes in gene transcription are required for the establishment of LTP. [•] Bdnf and c-fos are highly regulated in response to neuronal activity. [•] Changes in histone postranslational modifications occur during learning paradigms. [•] Neural activity induces active DNA methylation and demethylation. [•] TET proteins and cytosine hydroxymethylation are new mechanisms regulating memory. [Copyright &y& Elsevier]

Mounting evidence has recently underscored the importance of DNA methylation in normal brain functions. DNA methylation machineries are responsible for dynamic regulation of methylation patterns in discrete brain regions. In addition to methylation of cytosines in genomic DNA (5-methylcytosine; 5mC), other forms of modified cytosines, such as 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, can potentially act as epigenetic marks that regulate gene expression. Importantly, epigenetic modifications require cognate binding proteins to read and translate information into gene expression regulation. Abnormal or incorrect interpretation of DNA methylation patterns can cause devastating consequences, including mental illnesses and neurological disorders. Although DNA methylation was generally considered to be a stable epigenetic mark in post-mitotic cells, recent studies have revealed dynamic DNA modifications in neurons. Such reversibility of 5mC sheds light on potential mechanisms underlying some neurological disorders and suggests a new route to correct aberrant methylation patterns associated with these disorders. [ABSTRACT FROM AUTHOR]

Prior to 2009, 5-methylcytosine (5-mC) was thought to be the only biologically significant cytosine modification in mammalian DNA. With the discovery of the TET enzymes, which convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), however, intense interest has emerged in determining the biological function of 5-hmC. Here, we review the techniques used to study 5-hmC and evidence that alterations to 5-hmC physiology play a functional role in the molecular pathogenesis of human cancers. [ABSTRACT FROM AUTHOR]

Highlights: [•] Ten-eleven translocation (TET) enzymes convert 5-mC to 5-hmC. [•] 5hmC can be repaired by thymine DNA glycosylase (TDG). [•] miR-29a targets to Tet1-3 and TDG mRNA and influences global 5hmC. [•] miR-29 can modulate epigenetics by targeting Tets and TDG. [ABSTRACT FROM AUTHOR]

Abstract: DNA methylation plays an important role in the regulation of gene expression, as it is the first epigenetic modification to take place on a given DNA strand. Several factors may directly or indirectly regulate the dynamic distribution of DNA methylation and demethylation between intergenic and intragenic gene regions, thereby controlling gene expression. CpG islands have direct implications for the understanding of DNA methylation patterns in normal conditions and in some common disease states, including cancer. Here, we summarize several recent studies on the genome-wide distribution of DNA methylation and demethylation and their related factors, and we discuss the potential of DNA methylation and demethylation patterns to contribute to gene transcription patterns in tumorigenesis. [Copyright &y& Elsevier]

Ascorbate (vitamin C) is an essential micronutrient in humans. The severe chronic deficiency of ascorbate, termed scurvy, has long been associated with increased susceptibility to infections. How ascorbate affects the immune system at the cellular and molecular levels remained unclear. From a micronutrient analysis, we identified ascorbate as a potent enhancer for antibody response by facilitating the IL-21/STAT3-dependent plasma cell differentiation in mouse and human B cells. The effect of ascorbate is unique as other antioxidants failed to promote plasma cell differentiation. Ascorbate is especially critical during early B cell activation by poising the cells to plasma cell lineage without affecting the proximal IL-21/STAT3 signaling and the overall transcriptome. As a cofactor for epigenetic enzymes, ascorbate facilitates TET2/3-mediated DNA modification and demethylation of multiple elements at the Prdm1 locus. DNA demethylation augments STAT3 association at the Prdm1 promoter and a downstream enhancer, thus ensuring efficient gene expression and plasma cell differentiation. The results suggest that an adequate level of ascorbate is required for antibody response and highlight how micronutrients may regulate the activity of epigenetic enzymes to regulate gene expression. Our findings imply that epigenetic enzymes can function as sensors to gauge the availability of metabolites and influence cell fate decisions., Competing Interests: HC, AA, FL, MH, EJ, EG, JY, RB, QM, HG, DW, FH, CL No competing interests declared, (© 2022, Chen, Almonte-Loya et al.)

DNA methylation at the fifth position of cytosine (5mC) is one of the most studied epigenetic mechanisms essential for the control of gene expression and for many other biological processes including genomic imprinting, X chromosome inactivation and genome stability. Over the last years, accumulating evidence suggest that DNA methylation is a highly dynamic mechanism driven by a balance between methylation by DNMTs and TET-mediated demethylation processes. However, one of the main challenges is to understand the dynamics underlying steady state DNA methylation levels. In this review article, we give an overview of the latest advances highlighting DNA methylation as a dynamic cycling process with a continuous turnover of cytosine modifications. We describe the cooperative actions of DNMT and TET enzymes which combine with many additional parameters including chromatin environment and protein partners to govern 5mC turnover. We also discuss how mathematical models can be used to address variable methylation levels during development and explain cell-type epigenetic heterogeneity locally but also at the genome scale. Finally, we review the therapeutic implications of these discoveries with the use of both epigenetic clocks as predictors and the development of epidrugs that target the DNA methylation/demethylation machinery. Together, these discoveries unveil with unprecedented detail how dynamic is DNA methylation during development, underlying the establishment of heterogeneous DNA methylation landscapes which could be altered in aging, diseases and cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Turpin and Salbert.)

Abstract: Cytosine methylation is an epigenetically propagated DNA modification that can modify how the DNA molecule is recognized and expressed. DNA methylation undergoes extensive reprogramming during mammalian embryogenesis and is directly linked to the regulation of pluripotency and cellular identity. Studying its regulation is also important for a better understanding of the many diseases that show epigenetic deregulations, in particular, cancer. In the recent years, a lot of progress has been made to characterize the profiles of DNA methylation at the genome level, which revealed that patterns of DNA methylation are highly dynamic between cell types. Here, we discuss the importance of DNA methylation for genome regulation and the mechanisms that remodel the DNA methylome during mammalian development, in particular the involvement of the rediscovered modified base 5-hydroxymethylcytosine. [Copyright &y& Elsevier]

Abstract: It is well known that water constitutes an important contamination route for microorganisms. This is especially true for Aeromonas which are widespread in untreated and treated waters. In this study, Portuguese untreated waters not regularly monitored were screened for the presence and diversity of aeromonads. A total of 206 isolates were discriminated by RAPD-PCR and 80 distinct strains were identified by gyrB based phylogenetic analysis. The most frequently detected species were Aeromonas hydrophila, Aeromonas bestiarum and Aeromonas media. The antibiotic susceptibility profile of these strains was determined and showed a typical profile of the genus. Nonetheless, the percentage of resistant strains to tetracycline, chloramphenicol and/or trimethoprim/sulfamethoxazole was lower than that reported for clinical isolates and isolates recovered from aquacultures and other environments historically subjected to antibiotic contamination. This suggests that the existence of such pressures in those environments selects for resistant Aeromonas. A similar trend for integron presence was found. Genes coding for CphA and TEM, and tet(A), (E), (C) or (D) genes were found in 28%, 1%, and 10% of the strains, respectively. 10% of the strains contained an integron. Variable regions of seven class 1 integrons and one class 2 integron were characterised. Furthermore, strains displayed virulence related phenotypes such as extracellular lipolytic and proteolytic activities as well as aerolysin related genes (43% of strains). The ascV and aexT genes were found in 16% and 3% of strains respectively and, in some cases, concomitantly in the same specimen. This study shows that diverse Aeromonas spp. presenting distinct antibiotic resistance features and putative virulence traits are frequently present in waters for human and animal consumption in Portugal. Genes associated to antibiotic resistance and microbial virulence previously identified in organisms with human health significance were detected in these aeromonads, suggesting that these waters may act as a pivotal route for infections. [Copyright &y& Elsevier]

5-Methylcytosine (5mC) in genomic DNA has important epigenetic functions in embryonic development and tumor biology. 5-Hydroxymethylcytosine (5hmC) is generated from 5mC by the action of the TET (Ten-Eleven-Translocation) enzymes and may be an intermediate to further oxidation and finally demethylation of 5mC. We have used immunohistochemistry (IHC) and isotope-based liquid chromatography mass spectrometry (LC-MS) to investigate the presence and distribution of 5hmC in human brain and brain tumors. In the normal adult brain, IHC identified 61.5% 5hmC positive cells in the cortex and 32.4% 5hmC in white matter (WM) areas. In tumors, positive staining of cells ranged from 1.1% in glioblastomas (GBMs) (WHO Grade IV) to 8.9% in Grade I gliomas (pilocytic astrocytomas). In the normal adult human brain, LC-MS also showed highest values in cortical areas (1.17% 5hmC/dG [deoxyguanosine]), in the cerebral WM we measured around 0.70% 5hmC/dG. 5hmC levels were related to tumor differentiation, ranging from lowest values of 0.078% 5hmC/dG in GBMs (WHO Grade IV) to 0.24% 5hmC/dG in WHO Grade II diffuse astrocytomas. 5hmC measurements were unrelated to 5mC values. We find that the number of 5hmC positive cells and the amount of 5hmC/dG in the genome that has been proposed to be related to pluripotency and lineage commitment in embryonic stem cells is also associated with brain tumor differentiation and anaplasia. [ABSTRACT FROM AUTHOR]

Over the past few decades, DNA methylation at the 5-position of cytosine (5-methylcytosine, 5mC) has emerged as an important epigenetic modification that plays essential roles in development, aging and disease. However, the mechanisms controlling 5mC dynamics remain elusive. Recent studies have shown that ten-eleven translocation (Tet) proteins can catalyze 5mC oxidation and generate 5mC derivatives, including 5- hydroxymethylcytosine (5hmC). The exciting discovery of these novel 5mC derivatives has begun to shed light on the dynamic nature of 5mC, and emerging evidence has shown that Tet family proteins and 5hmC are involved in normal development as well as in many diseases. In this Primer we provide an overview of the role of Tet family proteins and 5hmC in development and cancer. [ABSTRACT FROM AUTHOR]

Transgenic and conditional knockout mouse models play an important role in biomedical research and their use has grown exponentially in the last 5-10 years. Generating conditional knockouts often requires breeding multiple alleles onto the background of a single mouse or group of mice. Breeding these mice depends on parental genotype, litter size, transmission frequency, and the number of breeding rounds. Therefore, a well planned breeding strategy is critical for keeping costs to a minimum. However, designing a viable breeding strategy can be challenging. With so many different variables this would be an ideal task for a computer program. To facilitate this process, we created a Java-based program called Conditional Allele Mouse Planner (CAMP). CAMP is designed to provide an estimate of the number of breeders, amount of time, and costs associated with generating mice of a particular genotype. We provide a description of CAMP, how to use it, and offer it freely as an application. [ABSTRACT FROM AUTHOR]

Bacterial pathogens that are multi-drug resistant compromise the effectiveness of treatment when they are the causative agents of infectious disease. These multi-drug resistance mechanisms allow bacteria to survive in the presence of clinically useful antimicrobial agents, thus reducing the efficacy of chemotherapy towards infectious disease. Importantly, active multi-drug efflux is a major mechanism for bacterial pathogen drug resistance. Therefore, because of their overwhelming presence in bacterial pathogens, these active multi-drug efflux mechanisms remain a major area of intense study, so that ultimately measures may be discovered to inhibit these active multi-drug efflux pumps. [ABSTRACT FROM AUTHOR]

Abstract: This paper describes the design and implementation of a self-tuning inductive powering system conceived for biomedical applications. The circuit operates at 1MHz and delivers 380 mW to the implant with an efficiency of 50%, at a distance of 1cm. Absorption modulation is used to monitor the circuit parameters allowing the system to deal with distance increases up to 5cm as well as small coil misalignments. The automatic-tuning system adjusts the configuration of the coil driver depending on the self-monitored coupling, acting on a bank of switchable capacitors with a pattern defined by the received data. It is demonstrated that the implemented tuning strategy boosts the transmitted power by a factor two. In addition, the combination of tuning and smart power regulation was proven to sensibly increase the system efficiency by maintaining a constant energy level at the secondary. [Copyright &y& Elsevier]

Methylation of DNA and histones in chromatin has been implicated in numerous biological processes. For many years, methylation has been recognized as static and stable modification, as compared with other covalent modifications of chromatin. Recently, however, several mechanisms have been demonstrated to be involved in demethylation of chromatin, suggesting that chromatin methylation is more dynamically regulated. One chemical reaction that mediates demethylation of both DNA and histones is hydroxylation, catalysed by Fe(II) and α-ketoglutarate (KG)-dependent hydroxylase/dioxygenase. Given that methylation of chromatin is an important epigenetic mark involved in fundamental biological processes such as cell fate determination, understanding how chromatin methylation is dynamically regulated has implications for human diseases and regenerative medicine. [ABSTRACT FROM PUBLISHER]

Abstract: Escherichia coli is used to assess the hygienic quality of food products and the dissemination of antimicrobial resistance. In particular, tetracycline-resistant E. coli can be chosen as an indicator of antibiotic resistant bacteria because it has a high frequency of occurrence. The purpose of this study was to investigate the distribution and transfer of tetracycline resistance determinants in meatborne E. coli. A total of 121 tetracycline-resistant E. coli isolates were collected from meat and meat products (raw meat, fish, and processed foods) from 2004 to 2006 in Korea. Among these isolates, tet(A) (52.4%) was the most frequent tetracycline resistance determinant, followed by tet(B) (41.3%), whereas tet(C) (1.7%) and tet(D) (0.8%) were less frequently identified. Two isolates (1.6%) contained two tet genes simultaneously, tet(A) and tet(B). Minimal inhibitory concentrations (MICs) to tetracycline family antibiotics, such as tetracycline, minocycline, doxycycline, oxytetracycline, and chlortetracycline were higher for isolates carrying the tet(B) gene compared to isolates carrying tet(A) (P <0.0001). Conjugation experiments were performed by the broth mating method; 119 isolates (98.3%) containing at least one of the tet genes were shown to transfer tetracycline resistance to recipient E. coli J53. Also, we observed high diversity of tetracycline-resistant E. coli isolates in meat and meat products in Korea by using XbaI pulsed-field gel electrophoresis (PFGE) typing. This study suggests that the high prevalence of tetracycline-resistant E. coli in meat may be due to the high transferability of tet determinants. [Copyright &y& Elsevier]

The article presents a study which analyzes the antibiotic susceptibility of bifidobacterial strains spread in the Japanese market. The study used the broth microdilution method to test 23 strains such as probiotic isolates from foods, pharmaceuticals, and supplements. Moreover, it found that strains were susceptible to ampicillin, chloramphenicol and vancomycin, as well as, linezolid.

Epigenetic modifications include DNA methylation, DNA demethylation along with the major role fulfilled by TET protein. Epigenetic modifications refer to the regulation of gene expression without the alteration of the DNA sequence. Some of the most common epigenetic modifications include DNA methylation and demethylation, as well as the functional role of TET proteins. Epigenetic alterations are heritable traits, therefore one of the key elements to understanding the mechanisms of cancer development is to further our knowledge on the role and function of epigenetic modifications. This mini-review takes into consideration the overview of the literature on the impact of epigenetic changes in cancer development, especially in the development of CC. Researchers believe that certain compounds are capable of inhibiting the process of DNA methylation and may play an important role in future cancer therapy. [ABSTRACT FROM AUTHOR]

Earthworms are well-established model organisms for testing the effects of heavy metal pollution. How DNA methylation affects cadmium (Cd) detoxification processes such as the expression of metallothionein 2 (MT2), however, is largely unknown. We therefore exposed Lumbricus terrestris to 200 mg concentrations of Cd and 5-aza-2′-deoxycytidine (Aza), a demethylating agent, and sampled tissue and coelomocytes, cells of the innate immune system, for 48 h. MT2 transcription significantly increased in the Cd- and Cd-Aza-treated groups. In tissue samples, a significant decrease in MT2 in the Aza-treated group was detected, showing that Aza treatment inhibits basal MT2 gene activity but has no effect on Cd-induced MT2 levels. Although Cd repressed the gene expression of DNA-(cytosine-5)-methyltransferase-1 (DNMT1), which is responsible for maintaining DNA methylation, DNMT activity was unchanged, meaning that methylation maintenance was not affected in coelomocytes. The treatment did not influence DNMT3, which mediates de novo methylation, TET gene expression, which orchestrates demethylation, and global levels of hydroxymethylcytosine (5hmC), a product of the demethylation process. Taken together, this study indicates that Aza inhibits basal gene activity, in contrast to Cd-induced MT2 gene expression, but does not affect global DNA methylation. We therefore conclude that Cd detoxification based on the induction of MT2 does not relate to DNA methylation changes. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a genetically heterogeneous and frequently fatal malignancy. The ten-eleven translocation (TET)-mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we find that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, are verified in AML cells in vitro and mouse and human AML models in vivo. OPA1-induced activation of OPRM1 signaling enhances the transcription of TET2 and thus activates both catalytic-dependent and -independent functions of TET2. Notably, AMLs with TET2 mutations or chemotherapy resistance are sensitive to OPA1 as well. Our results reveal the OPRM1- TET2 regulatory axis in AML and suggest that opioid agonists, particularly OPA1, a US Food and Drug Administration (FDA)-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2 -mutated and chemotherapy-resistant AMLs, which have a poor prognosis. [Display omitted] • Opioid signaling agonists have therapeutic potential in AML • Opioid signaling activates TET2 transcription and increases global 5hmC level • TET2 enzymatic activity-dependent and -independent functions in OPA1 response • The OPRM1- TET2 regulatory axis is involved in AML The regulatory pathway of the TET-mediated DNA demethylation remains unclear in acute myeloid leukemia (AML). Zhao et al. report the beneficial therapeutic effects of opioid-receptor agonists, especially loperamide hydrochloride (OPA1) in AML, as OPA1 induces the activation of the OPRM1-TET2 regulatory axis in TET2-mutated and chemotherapy-resistant AML. [ABSTRACT FROM AUTHOR]

Dysregulation of DNA methylation in B cells has been observed during their neoplastic transformation and therefore closely associated with various B-cell malignancies including multiple myeloma (MM), a malignancy of terminally differentiated plasma cells. Emerging evidence has unveiled pronounced alterations in DNA methylation in MM, including both global and gene-specific changes that can affect genome stability and gene transcription. Moreover, dysregulated expression of DNA methylation-modifying enzymes has been related with myelomagenesis, disease progression, and poor prognosis. However, the functional roles of the epigenetic abnormalities involving DNA methylation in MM remain elusive. In this article, we review current understanding of the alterations in DNA methylome and DNA methylation modifiers in MM, particularly focusing on DNA methyltransferases (DNMTs) and tet methylcytosine dioxygenases (TETs). We also discuss how these DNA methylation modifiers may be regulated and function in MM cells, therefore providing a rationale for developing novel epigenetic therapies targeting DNA methylation in MM. [ABSTRACT FROM AUTHOR]

Development of antimicrobial resistance in food animals receiving antimicrobials has been well documented among bacterial isolates, especially pathogens, but information on development of antimicrobial resistance at the microbial community level during long-term feeding of antimicrobials is lacking. The objective of this study was to examine the association between inclusion of tylosin in feed and occurrence of resistance to macrolide-lincosamide-streptogramjn B (MLSB) in the entire fecal microbial communities of beef cattle over a feeding study of 168 d. A completely randomized design included 6 pens housed together in 1 barn, with each pen housing 10 to 11 steers. The control and tylosin groups each had 3 pens, with the former receiving no antimicrobial whereas the latter received both tylosin and monensin (11 and 29.9 mgI kg of feed, respectively, DM) in feed. The abundance of genes conferring resistance to MLSB (erm genes) and tetracyclines (tet genes) were quantified using class-specific, real-time PCR assays. The abundances of erm and tet genes were analyzed with pens as experimental units using the MIXED procedure of SAS. Correlations between abundance of different resistance genes were calculated using the CORR procedure of SAS. We identified 4 classes (B, F, T, and X) of erm genes in fresh fecal samples collected at wk 2, 17, and 21 of feeding. From wk 2 to 17, the abundance of erm(T) and erm(X) increased (P< 0.05), whereas that of erm(B) and erm(F) did not. The abundance of the erm genes did not further change from wk 17 to 21. The tet(A/C), tet(G), and tet gene variants encoding ribosomal protection proteins (including classes M, 0, P, Q, S, T, and W) appeared to be co-selected by tylosin feeding. Such co-selection of multiresistance at community level by one antimicrobial drug used in animals has the important implication that future studies should examine resistance to not only the antimicrobials used in animals, but also other antimicrobials, especially those used in human medicine, to fully assess the potential risk associated with antimicrobial use in animals. Both the erm and tet genes appeared to be disseminated among the microbial populations in all steers housed together. [ABSTRACT FROM AUTHOR]

It is well established that gene expression in eukaryotes is controlled by sequence-dependent binding of trans-acting proteins to regulatory elements like promoters, enhancers or silencers. A less well understood level of gene regulation is governed by the various structural and functional states of chromatin, which have been ascribed to changes in covalent modification of core histone proteins. And, much on how topological domains in the genome take part in establishing and maintaining distinct gene expression patterns is still unknown. Here we present a set of regulatory proteins that allow to reversibly alter the DNA structure in vivo and in vitro by adding low molecular weight effectors that control their oligomerization and DNA binding. Using this approach, we completely regulate the activity of an SV40 enhancer in HeLa cells by reversible loop formation to topologically separate it from the promoter. This result establishes a new mechanism for DNA-structure-dependent gene regulation in vivo and provides evidence supporting the structural model of insulator function. [ABSTRACT FROM AUTHOR]

The vertebrate transcription factor CTCF is not only involved in transcriptional activation, insulation and genomic imprinting, but also in transcriptional repression. Sequence motifs mediating these activities have not been identified so far. We have mapped a short repression motif to residues 150–170 within the N-terminal domain of CTCF. This motif is active in HeLa, HEK293 and COS-7 cell lines where it is both sufficient and necessary for silencing either an SV40-, or a CMV-enhancer. It also represses the basal activity of an SV40 core promoter. Since this autonomous repression motif displays no sequence similarity to any other regulatory protein, it represents a yet unknown co-repressor recruiting motif. [Copyright &y& Elsevier]

Peripheral and tissue-specific alterations in global DNA methylation (5-methylcytosine (5mC)) and DNA hydroxymethylation (5-hydroxymethylcytosine (5hmC)) profiles have been identified as both biomarkers for disease prediction and as hallmarks of dysregulated localized gene networks. Global and gene-specific epigenetic alterations in the 5mC profiles have shown widespread implications in the etiology of polycystic ovary syndrome (PCOS). However, there has been no study in PCOS that integrates the quantification of 5mC and 5hmC signatures alongside the expression levels of DNA methylating and demethylating enzymes as respective indicators of methylation and demethylation pathways. Having previously shown that the 5mC signatures are not substantially altered in PCOS, we assessed the global 5hmC levels in peripheral blood leukocytes and cumulus granulosa cells (CGCs) of 40 controls and 40 women with PCOS. This analysis revealed higher 5hmC levels in CGCs of PCOS women, indicating a more dominant demethylation pathway. Furthermore, we assessed the transcript and protein expression levels of DNA demethylating and methylating enzymes, i.e. ten-eleven translocation methylcytosine dioxygenases (TET1, TET2, TET3) and DNA methyltransferases (DNMT1, DNMT3A and DNMT3B), respectively, in CGCs. The relative transcript and protein expression levels of all three TETs were found to be higher in women with PCOS, and the TET mRNA expression profiles were positively correlated with 5hmC levels in CGCs. Also, all three DNMT genes showed altered transcript expression in PCOS, although only the downregulated DNMT3A transcript was correlated with decreasing 5mC levels. At the protein level, the expression of DNMT1 (maintenance methylation enzyme) was higher, while that of DNMT3A (de novo methylation enzyme) was found to be lower in PCOS compared to controls. Overall, these results indicate that DNA methylation changes in CGCs of PCOS women may arise partly due to intrinsic alterations in the transcriptional regulation of TETs and DNMT3A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

5-Hydroxymethylcytosine (5hmC) has recently been found that plays an important role in many diseases; however, there are still few studies in the field of stroke. The purpose of this review is to introduce the influence and function of 5hmC in stroke, in order for more people can study it. In this review, we introduced the role of 5hmC in ischemia and hemorrhage stroke, and summarized the possible therapeutic prospects of 5hmC in stroke. In conclusion, we suggest that 5hmC may serve as a biomarker or therapeutic target for the treatment of stroke., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Poly(ADP-ribosyl)ation (PARylation), a posttranslational modification introduced by PARP-1 and PARP-2, has first been implicated in DNA demethylation due to its role in base excision repair. Recent evidence indicates a direct influence of PARP-dependent PARylation on TET enzymes which catalyse hydroxymethylation of DNA-the first step in DNA demethylation. However, the exact nature of influence that PARylation exerts on TET activity is still ambiguous. In our recent study, we have observed a negative influence of PARP-1 on local TET-mediated DNA demethylation of a single gene and in this study, we further explore PARP-TET interplay., Results: Expanding on our previous work, we show that both TET1 and TET2 can be in vitro PARylated by PARP-1 and PARP-2 enzymes and that TET1 PARylation negatively affects the TET1 catalytic activity in vitro. Furthermore, we show that PARylation inhibits TET-mediated DNA demethylation at the global genome level in cellulo., Conclusions: According to our findings, PARP inhibition can positively influence TET activity and therefore affect global levels of DNA methylation and hydroxymethylation. This gives a strong rationale for future examination of PARP inhibitors' potential use in the therapy of cancers characterised by loss of 5-hydroxymethylcytosine., (© 2022. The Author(s).)

Ten-Eleven Translocation (TET) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) leading to a dynamic epigenetic state of DNA that can influence transcription and chromatin organization. While TET proteins interact with complexes involved in transcriptional repression and activation, the overall understanding of the molecular mechanisms involved in TET-mediated regulation of gene expression still remains limited. Here, we show that TET proteins interact with the chromatin remodelling protein lymphoid-specific helicase (LSH/HELLS) in vivo and in vitro . In mouse embryonic fibroblasts (MEFs) and embryonic stem cells (ESCs) knock out of Lsh leads to a significant reduction of 5-hydroxymethylation amount in the DNA. Whole genome sequencing of 5hmC in wild-type versus Lsh knock-out MEFs and ESCs showed that in absence of Lsh , some regions of the genome gain 5hmC while others lose it, with mild correlation with gene expression changes. We further show that differentially hydroxymethylated regions did not completely overlap with differentially methylated regions indicating that changes in 5hmC distribution upon Lsh knock-out are not a direct consequence of 5mC decrease. Altogether, our results suggest that LSH, which interacts with TET proteins, contributes to the regulation of 5hmC levels and distribution in MEFs and ESCs.

The Coefficients H technique (also called the H-technique), developed by Patarin circa 1991, is a tool used to obtain the upper bounds on distinguishing advantages. This tool is known to provide relatively simple and (in some cases) tight bound proofs in comparison to some other well-known tools, such as the game-playing technique and random systems methodology. In this systematization of knowledge (SoK) paper, we aim to provide a brief survey on the H-technique. The SoK is presented in four parts. First, we redevelop the necessary nomenclature and tools required to study the security of any symmetric-key design, especially in the H-technique setting. Second, we provide a full description of the H-technique and some related tools. Third, we present (simple) H-technique-based proofs for some popular symmetric-key designs, across different paradigms. Finally, we show that the H-technique can actually provide optimal bounds on distinguishing advantages.

DNA methylation is one of the most important epigenetic mechanisms to regulate gene expression, which is highly dynamic during development and specifically maintained in somatic cells. Aberrant DNA methylation patterns are strongly associated with human diseases including cancer. How are the cell-specific DNA methylation patterns established or disturbed is a pivotal question in developmental biology and cancer epigenetics. Currently, compelling evidence has emerged that long non-coding RNA (lncRNA) mediates DNA methylation in both physiological and pathological conditions. In this review, we provide an overview of the current understanding of lncRNA-mediated DNA methylation, with emphasis on the roles of this mechanism in cancer, which to the best of our knowledge, has not been systematically summarized. In addition, we also discuss the potential clinical applications of this mechanism in RNA-targeting drug development., (© 2022. The Author(s).)