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Psychostimulants regulate behavioral responses in zebrafish via epigenetic mechanisms. We have previously shown that DNA methylation and histone deacetylase (HDAC) inhibition abolish nicotine-induced conditioned place preference (CPP) but little is known about the role of histone methylation in addictive-like behaviors. To assess the influence of histone methylation on nicotine-CPP, zebrafish were treated with a histone (H3) lysine-9 (K9) dimethyltransferase G9a/GLP inhibitor, BIX-01294 (BIX), which was administered before conditioning sessions. We observed a dual effect of the inhibitor BIX: at high doses inhibited while at low doses potentiated nicotine reward. Transcriptional expression of α6 and α7 subunits of the nicotinic acetylcholine receptor and of G9a, DNA methyl transferase-3, and HDAC-1 was upregulated in zebrafish with positive scores for nicotine-CPP. Changes in relative levels of these mRNA molecules reflected the effects of BIX on nicotine reward. BIX treatment per sé did not affect transcriptional levels of epigenetic enzymes that regulate trimethylation or demethylation of H3. BIX reduced H3K9me2 protein levels in a dose-dependent manner in key structures of the reward pathway. Thus, our findings indicated that different doses of BIX differentially affect nicotine CPP via strong or weak inhibition of G9a/GLP activity. Additionally, we found that the lysine demethylase inhibitor daminozide abolished nicotine-CPP and drug seeking. Our data demonstrate that H3 methylation catalyzed by G9a/GLP is involved in nicotine-CPP induction. Dimethylation of K9 at H3 is an important epigenetic modification that should be considered as a potential therapeutic target to treat nicotine reward and perhaps other drug addictions. [ABSTRACT FROM AUTHOR]

Abstract Histone lysine methylation is thought to play a role in the pathogenesis of rheumatoid arthritis (RA). We previously reported aberrant expression of the gene encoding mixed-lineage leukemia 1 (MLL1), which catalyzes methylation of histone H3 lysine 4 (H3K4), in RA synovial fibroblasts (SFs). The aim of this study was to elucidate the involvement of MLL1 in the activated phenotype of RASFs. SFs were isolated from synovial tissues obtained from patients with RA or osteoarthritis (OA) during total knee joint replacement. MLL1 mRNA and protein levels were determined after stimulation with tumor necrosis factor α (TNFα). We also examined changes in trimethylation of H3K4 (H3K4me3) levels in the promoters of RA-associated genes (matrix-degrading enzymes, cytokines, and chemokines) and the mRNA levels upon small interfering RNA-mediated depletion of MLL1 in RASFs. We then determined the levels of H3K4me3 and mRNAs following treatment with the WD repeat domain 5 (WDR5)/MLL1 inhibitor MM-102. H3K4me3 levels in the gene promoters were also compared between RASFs and OASFs. After TNFα stimulation, MLL1 mRNA and protein levels were higher in RASFs than OASFs. Silencing of MLL1 significantly reduced H3K4me3 levels in the promoters of several cytokine (interleukin-6 [IL-6], IL-15) and chemokine (C–C motif chemokine ligand 2 [CCL2], CCL5, C-X-C motif chemokine ligand 9 [CXCL9], CXCL10, CXCL11, and C-X3-C motif chemokine ligand 1 [CX3CL1]) genes in RASFs. Correspondingly, the mRNA levels of these genes were significantly decreased. MM-102 significantly reduced the promoter H3K4me3 and mRNA levels of the CCL5, CXCL9, CXCL10, and CXCL11 genes in RASFs. In addition, H3K4me3 levels in the promoters of the IL-6, IL-15, CCL2, CCL5, CXCL9, CXCL10, CXCL11, and CX3CL1 genes were significantly higher in RASFs than OASFs. Our findings suggest that MLL1 regulates the expression of particular cytokines and chemokines in RASFs and is associated with the pathogenesis of RA. These results could lead to new therapies for RA.

Abstract Genes containing the SET domain can catalyse histone lysine methylation, which in turn has the potential to cause changes to chromatin structure and regulation of the transcription of genes involved in diverse physiological and developmental processes. However, the functions of SET domain-containing (StSET) genes in potato still need to be studied. The objectives of our study can be summarized as in silico analysis to (i) identify StSET genes in the potato genome, (ii) systematically analyse gene structure, chromosomal distribution, gene duplication events, promoter sequences, and protein domains, (iii) perform phylogenetic analyses, (iv) compare the SET domain-containing genes of potato with other plant species with respect to protein domains and orthologous relationships, (v) analyse tissue-specific expression, and (vi) study the expression of StSET genes in response to drought and heat stresses. In this study, we identified 57 StSET genes in the potato genome, and the genes were physically mapped onto eleven chromosomes. The phylogenetic analysis grouped these StSET genes into six clades. We found that tandem duplication through sub-functionalisation has contributed only marginally to the expansion of the StSET gene family. The protein domain TDBD (PFAM ID: PF16135) was detected in StSET genes of potato while it was absent in all other previously studied species. This study described three pollen-specific StSET genes in the potato genome. Expression analysis of four StSET genes under heat and drought in three potato clones revealed that these genes might have non-overlapping roles under different abiotic stress conditions and durations. The present study provides a comprehensive analysis of StSET genes in potatoes, and it serves as a basis for further functional characterisation of StSET genes towards understanding their underpinning biological mechanisms in conferring stress tolerance.

Histone lysine methylation is thought to play a role in the pathogenesis of rheumatoid arthritis (RA). We previously reported aberrant expression of the gene encoding mixed-lineage leukemia 1 (MLL1), which catalyzes methylation of histone H3 lysine 4 (H3K4), in RA synovial fibroblasts (SFs). The aim of this study was to elucidate the involvement of MLL1 in the activated phenotype of RASFs. SFs were isolated from synovial tissues obtained from patients with RA or osteoarthritis (OA) during total knee joint replacement. MLL1 mRNA and protein levels were determined after stimulation with tumor necrosis factor α (TNFα). We also examined changes in trimethylation of H3K4 (H3K4me3) levels in the promoters of RA-associated genes (matrix-degrading enzymes, cytokines, and chemokines) and the mRNA levels upon small interfering RNA-mediated depletion of MLL1 in RASFs. We then determined the levels of H3K4me3 and mRNAs following treatment with the WD repeat domain 5 (WDR5)/MLL1 inhibitor MM-102. H3K4me3 levels in the gene promoters were also compared between RASFs and OASFs. After TNFα stimulation, MLL1 mRNA and protein levels were higher in RASFs than OASFs. Silencing of MLL1 significantly reduced H3K4me3 levels in the promoters of several cytokine (interleukin-6 [IL-6], IL-15) and chemokine (C–C motif chemokine ligand 2 [CCL2], CCL5, C-X-C motif chemokine ligand 9 [CXCL9], CXCL10, CXCL11, and C-X3-C motif chemokine ligand 1 [CX3CL1]) genes in RASFs. Correspondingly, the mRNA levels of these genes were significantly decreased. MM-102 significantly reduced the promoter H3K4me3 and mRNA levels of the CCL5, CXCL9, CXCL10, and CXCL11 genes in RASFs. In addition, H3K4me3 levels in the promoters of the IL-6, IL-15, CCL2, CCL5, CXCL9, CXCL10, CXCL11, and CX3CL1 genes were significantly higher in RASFs than OASFs. Our findings suggest that MLL1 regulates the expression of particular cytokines and chemokines in RASFs and is associated with the pathogenesis of RA. These results could lead to new therapies for RA. [ABSTRACT FROM AUTHOR]

Genes containing the SET domain can catalyse histone lysine methylation, which in turn has the potential to cause changes to chromatin structure and regulation of the transcription of genes involved in diverse physiological and developmental processes. However, the functions of SET domain-containing (StSET) genes in potato still need to be studied. The objectives of our study can be summarized as in silico analysis to (i) identify StSET genes in the potato genome, (ii) systematically analyse gene structure, chromosomal distribution, gene duplication events, promoter sequences, and protein domains, (iii) perform phylogenetic analyses, (iv) compare the SET domain-containing genes of potato with other plant species with respect to protein domains and orthologous relationships, (v) analyse tissue-specific expression, and (vi) study the expression of StSET genes in response to drought and heat stresses. In this study, we identified 57 StSET genes in the potato genome, and the genes were physically mapped onto eleven chromosomes. The phylogenetic analysis grouped these StSET genes into six clades. We found that tandem duplication through sub-functionalisation has contributed only marginally to the expansion of the StSET gene family. The protein domain TDBD (PFAM ID: PF16135) was detected in StSET genes of potato while it was absent in all other previously studied species. This study described three pollen-specific StSET genes in the potato genome. Expression analysis of four StSET genes under heat and drought in three potato clones revealed that these genes might have non-overlapping roles under different abiotic stress conditions and durations. The present study provides a comprehensive analysis of StSET genes in potatoes, and it serves as a basis for further functional characterisation of StSET genes towards understanding their underpinning biological mechanisms in conferring stress tolerance. [ABSTRACT FROM AUTHOR]

The eukaryotic green alga Chromochloris zofingiensis is a reference organism for studying carbon partitioning and a promising candidate for the production of biofuel precursors. Recent transcriptome profiling transformed our understanding of its biology and generally algal biology, but epigenetic regulation remains understudied and represents a fundamental gap in our understanding of algal gene expression. Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) is a powerful tool for the discovery of such mechanisms, by identifying genome-wide histone modification patterns and transcription factor-binding sites alike. Here, we established a ChIP-Seq framework for Chr. zofingiensis yielding over 20 million high-quality reads per sample. The most critical steps in a ChIP experiment were optimized, including DNA shearing to obtain an average DNA fragment size of 250 bp and assessment of the recommended formaldehyde concentration for optimal DNA-protein cross-linking. We used this ChIP-Seq framework to generate a genome-wide map of the H3K4me3 distribution pattern and to integrate these data with matching RNA-Seq data. In line with observations from other organisms, H3K4me3 marks predominantly transcription start sites of genes. Our H3K4me3 ChIP-Seq data will pave the way for improved genome structural annotation in the emerging reference alga Chr. zofingiensis.

Summary: Histone lysine methylations (HLMs) are implicated in control of gene expression in different eukaryotes. However, the role of HLMs in regulating desirable crop traits and the enzymes involved in these modifications are poorly understood.We studied the functions of tomato histone H3 lysine methyltransferases SET Domain Group 33 (SDG33) and SDG34 in biotic and abiotic stress responses. SDG33 and SDG34 gene edited mutants were altered in H3K36 and H3K4 methylations, and expression of genes involved in diverse processes and responses to biotic and abiotic stimuli.The double but not the single mutants show resistance to the fungal pathogen Botrytis cinerea. Interestingly, single mutants were tolerant to drought and the double mutant showed superior tolerance and plant growth consistent with independent and additive functions. Mutants maintained higher water status during drought and improved recovery and survival after lapse of drought.Notably, diminution of H3K4 and H3K36 trimethylation and expression of negative regulators in challenged plants contributes to stress tolerance of the mutants. Mutations in SDG33 and SDG34 are likely to remove predisposition to biotic and abiotic stress by disrupting permissive transcriptional context promoting expression of negative regulatory factors. These allows improvement of stress and pathogen tolerance, without growth trade‐offs, through modification of histone epigenetic marks. [ABSTRACT FROM AUTHOR]

Wood frog (Rana sylvatica) freeze tolerance necessitates metabolic rate depression, where costly processes such as gene transcription are commonly suppressed. Epigenetic mechanisms, such as histone lysine methylation, have recently been implicated in hypometabolic states of various animals, although they are underreported in nervous tissues. In the present study, we track the expression of eight lysine methyltransferases, as well as the activity on, and abundance of putative histone products across the freeze–thaw cycle and freeze‐associated substresses (anoxia, dehydration) of wood frog brains. Our results suggest that hypomethylation of transcriptionally repressive H3K9 may be a key facet of metabolic recovery during the thawing of nervous tissue, which we speculate may have a positive effect on global gene transcription. Some nonhistone roles for lysine methylation are also proposed. [ABSTRACT FROM AUTHOR]

Histone methylation is an epigenetic change mediated by histone methyltransferase, and has been connected to the beginning and progression of several diseases. The most common ailments that affect the elderly are cardiovascular and cerebrovascular disorders. They are the leading causes of death, and their incidence is linked to vascular calcification (VC). The key mechanism of VC is the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like phenotypes, which is a highly adjustable process involving a variety of complex pathophysiological processes, such as metabolic abnormalities, apoptosis, oxidative stress and signalling pathways. Many researchers have investigated the mechanism of VC and related targets for the prevention and treatment of cardiovascular and cerebrovascular diseases. Their findings revealed that histone lysine methylation modification may play a key role in the various stages of VC. As a result, a thorough examination of the role and mechanism of lysine methylation modification in physiological and pathological states is critical, not only for identifying specific molecular markers of VC and new therapeutic targets, but also for directing the development of new related drugs. Finally, we provide this review to discover the association between histone methylation modification and VC, as well as diverse approaches with which to investigate the pathophysiology of VC and prospective treatment possibilities. [ABSTRACT FROM AUTHOR]

PTIP-associated protein 1 (PA1) is a unique component of MLL3/4 complexes, which are important mammalian histone 3 lysine 4 (H3K4) methyltransferases. PA1 has generated research interest due to its involvement in many essential biological processes such as adipogenesis, B cell class switch recombination, spermatogenesis, and embryonic development. In addition to the classical role of PA1 in H3K4 methylation, non-classical functions have also been discovered in recent studies. In this review, we systematically summarize the expression pattern of PA1 protein in humans and sort the specific molecular mechanism of PA1 in various biological processes. Meanwhile, we provide some new perspectives on the role of PA1 for future studies. A comprehensive understanding of the biological functions and molecular mechanisms of PA1 will facilitate the investigation of its complicated roles in transcriptional regulation. [ABSTRACT FROM AUTHOR]

Histone N-terminal tails of nucleosomes are the sites of complex regulation of gene expression through post-translational modifications. Among these modifications, histone methylation had long been associated with permanent gene inactivation until the discovery of Lys-specific demethylase (LSD1), which is responsible for dynamic gene regulation. There are more than 30 members of the Lys demethylase (KDM) family, and with exception of LSD1 and LSD2, all other KDMs possess the Jumonji C (JmjC) domain exhibiting demethylase activity and require unique cofactors, for example, Fe(II) and α-ketoglutarate. These cofactors have been targeted when devising KDM inhibitors, which may yield therapeutic benefit. KDMs and their counterpart Lys methyltransferases (KMTs) regulate multiple biological processes, including oncogenesis and inflammation. KDMs' functional interactions with retinoblastoma (Rb) and E2 factor (E2F) target promoters illustrate their regulatory role in cell cycle progression and oncogenesis. Recent findings also demonstrate the control of inflammation and immune functions by KDMs, such as KDM6B that regulates the pro-inflammatory gene expression and CD4+ T helper (Th) cell lineage determination. This review will highlight the mechanisms by which KDMs and KMTs regulate the target gene expression and how epigenetic mechanisms may be applied to our understanding of oral inflammation.

PTIP-associated protein 1 (PA1) is a unique component of MLL3/4 complexes, which are important mammalian histone 3 lysine 4 (H3K4) methyltransferases. PA1 has generated research interest due to its involvement in many essential biological processes such as adipogenesis, B cell class switch recombination, spermatogenesis, and embryonic development. In addition to the classical role of PA1 in H3K4 methylation, non-classical functions have also been discovered in recent studies. In this review, we systematically summarize the expression pattern of PA1 protein in humans and sort the specific molecular mechanism of PA1 in various biological processes. Meanwhile, we provide some new perspectives on the role of PA1 for future studies. A comprehensive understanding of the biological functions and molecular mechanisms of PA1 will facilitate the investigation of its complicated roles in transcriptional regulation.

Histone methylation is an epigenetic change mediated by histone methyltransferase, and has been connected to the beginning and progression of several diseases. The most common ailments that affect the elderly are cardiovascular and cerebrovascular disorders. They are the leading causes of death, and their incidence is linked to vascular calcification (VC). The key mechanism of VC is the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like phenotypes, which is a highly adjustable process involving a variety of complex pathophysiological processes, such as metabolic abnormalities, apoptosis, oxidative stress and signalling pathways. Many researchers have investigated the mechanism of VC and related targets for the prevention and treatment of cardiovascular and cerebrovascular diseases. Their findings revealed that histone lysine methylation modification may play a key role in the various stages of VC. As a result, a thorough examination of the role and mechanism of lysine methylation modification in physiological and pathological states is critical, not only for identifying specific molecular markers of VC and new therapeutic targets, but also for directing the development of new related drugs. Finally, we provide this review to discover the association between histone methylation modification and VC, as well as diverse approaches with which to investigate the pathophysiology of VC and prospective treatment possibilities.

Abstract The eukaryotic green alga Chromochloris zofingiensis is a reference organism for studying carbon partitioning and a promising candidate for the production of biofuel precursors. Recent transcriptome profiling transformed our understanding of its biology and generally algal biology, but epigenetic regulation remains understudied and represents a fundamental gap in our understanding of algal gene expression. Chromatin immunoprecipitation followed by deep sequencing (ChIP‐Seq) is a powerful tool for the discovery of such mechanisms, by identifying genome‐wide histone modification patterns and transcription factor‐binding sites alike. Here, we established a ChIP‐Seq framework for Chr. zofingiensis yielding over 20 million high‐quality reads per sample. The most critical steps in a ChIP experiment were optimized, including DNA shearing to obtain an average DNA fragment size of 250 bp and assessment of the recommended formaldehyde concentration for optimal DNA–protein cross‐linking. We used this ChIP‐Seq framework to generate a genome‐wide map of the H3K4me3 distribution pattern and to integrate these data with matching RNA‐Seq data. In line with observations from other organisms, H3K4me3 marks predominantly transcription start sites of genes. Our H3K4me3 ChIP‐Seq data will pave the way for improved genome structural annotation in the emerging reference alga Chr. zofingiensis.

Abstract Background Dendrobium catenatum, as a precious Chinese herbal medicine, is an epiphytic orchid plant, which grows on the trunks and cliffs and often faces up to diverse environmental stresses. SET DOMAIN GROUP (SDG) proteins act as histone lysine methyltransferases, which are involved in pleiotropic developmental events and stress responses through modifying chromatin structure and regulating gene transcription, but their roles in D. catenatum are unknown. Results In this study, we identified 44 SDG proteins from D. catenatum genome. Subsequently, comprehensive analyses related to gene structure, protein domain organization, and phylogenetic relationship were performed to evaluate these D. catenatum SDG (DcSDG) proteins, along with the well-investigated homologs from the model plants Arabidopsis thaliana and Oryza sativa as well as the newly characterized 42 SDG proteins from a closely related orchid plant Phalaenopsis equestris. We showed DcSDG proteins can be grouped into eight distinct classes (I~VII and M), mostly consistent with the previous description. Based on the catalytic substrates of the reported SDG members mainly in Arabidopsis, Class I (E(z)-Like) is predicted to account for the deposition of H3K27me2/3, Class II (Ash-like) for H3K36me, Class III (Trx/ATX-like) for H3K4me2/3, Class M (ATXR3/7) for H3K4me, Class IV (Su (var)-like) for H3K27me1, Class V (Suv-like) for H3K9me, as well as class VI (S-ET) and class VII (RBCMT) for methylation of both histone and non-histone proteins. RNA-seq derived expression profiling showed that DcSDG proteins usually displayed wide but distinguished expressions in different tissues and organs. Finally, environmental stresses examination showed the expressions of DcASHR3, DcSUVR3, DcATXR4, DcATXR5b, and DcSDG49 are closely associated with drought-recovery treatment, the expression of DcSUVH5a, DcATXR5a and DcSUVR14a are significantly influenced by low temperature, and even 61% DcSDG genes are in response to heat shock. Conclusions This study systematically identifies and classifies SDG genes in orchid plant D. catenatum, indicates their functional divergence during the evolution, and discovers their broad roles in the developmental programs and stress responses. These results provide constructive clues for further functional investigation and epigenetic mechanism dissection of SET-containing proteins in orchids.

Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27-) and dismal (K4-/K27-) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation (EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease.

Background: Dendrobium catenatum, as a precious Chinese herbal medicine, is an epiphytic orchid plant, which grows on the trunks and cliffs and often faces up to diverse environmental stresses. SET DOMAIN GROUP (SDG) proteins act as histone lysine methyltransferases, which are involved in pleiotropic developmental events and stress responses through modifying chromatin structure and regulating gene transcription, but their roles in D. catenatum are unknown. Results: In this study, we identified 44 SDG proteins from D. catenatum genome. Subsequently, comprehensive analyses related to gene structure, protein domain organization, and phylogenetic relationship were performed to evaluate these D. catenatum SDG (DcSDG) proteins, along with the well-investigated homologs from the model plants Arabidopsis thaliana and Oryza sativa as well as the newly characterized 42 SDG proteins from a closely related orchid plant Phalaenopsis equestris. We showed DcSDG proteins can be grouped into eight distinct classes (I~VII and M), mostly consistent with the previous description. Based on the catalytic substrates of the reported SDG members mainly in Arabidopsis, Class I (E(z)-Like) is predicted to account for the deposition of H3K27me2/3, Class II (Ash-like) for H3K36me, Class III (Trx/ATX-like) for H3K4me2/3, Class M (ATXR3/7) for H3K4me, Class IV (Su (var)-like) for H3K27me1, Class V (Suv-like) for H3K9me, as well as class VI (S-ET) and class VII (RBCMT) for methylation of both histone and non-histone proteins. RNA-seq derived expression profiling showed that DcSDG proteins usually displayed wide but distinguished expressions in different tissues and organs. Finally, environmental stresses examination showed the expressions of DcASHR3, DcSUVR3, DcATXR4, DcATXR5b, and DcSDG49 are closely associated with drought-recovery treatment, the expression of DcSUVH5a, DcATXR5a and DcSUVR14a are significantly influenced by low temperature, and even 61% DcSDG genes are in response to heat shock. Conclusions: This study systematically identifies and classifies SDG genes in orchid plant D. catenatum, indicates their functional divergence during the evolution, and discovers their broad roles in the developmental programs and stress responses. These results provide constructive clues for further functional investigation and epigenetic mechanism dissection of SET-containing proteins in orchids. [ABSTRACT FROM AUTHOR]

Histone lysine methylation, which plays an important role in the regulation of gene expression, genome stability, chromosome conformation and cell differentiation, is a dynamic process that is collaboratively regulated by lysine methyltransferases (KMTs) and lysine demethylases (KDMs). LSD1, the first identified KDMs, catalyzes the demethylation of mono- and di-methylated H3K4 and H3K9. Here, we systematically investigated the effects of LSD1 knockdown on histone methylations. Surprisingly, in addition to H3K4 and H3K9, the methylation level on other histone lysines, such as H3K27, H3K36 and H3K79, are also increased. The expression of SOX2, E-cadherin and FoxA2 are increased upon LSD1 knockdown, and the methylation level of H3K4, H3K27 and H3K36 in the promoter region of these genes are all changed after LSD1 knockdown. Our results show that LSD1 knockdown has a broad effect on histone lysine methylation, which indicates that LSD1 regulates histone lysine methylation in collaboration with other KMTs and KDMs. [ABSTRACT FROM AUTHOR]

Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available genomics techniques, such as exome sequencing, have identified an increasing number of histone lysine methylation-related genes as intellectual disability-associated genes, which highlights the importance of accurate control of histone methylation during neurogenesis. However, given the functional diversity and complexity of histone methylation within the cell, the study of the molecular basis of histone methylation-related neurodevelopmental disorders is currently still in its infancy. Here, we review the latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders and propose possible therapeutic application of epigenetic compounds regulating histone methylation status for the treatment of these diseases. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms such as DNA methylation and histone methylation are critical regulators of gene transcription changes during memory consolidation. However, it is unknown how these epigenetic modifications coordinate control of gene expression following reactivation of a previously consolidated memory. Here, we found that retrieval of a recent contextual fear conditioned memory increased global levels of H3 lysine 4-trimethylation (H3K4me3) and DNA 5-hydroxymethylation (5hmC) in area CA1 of the dorsal hippocampus. Further experiments revealed increased levels of H3K4me3 and DNA 5hmC within a CpG-enriched coding region of the Npas4 , but not c-fos , gene. Intriguingly, retrieval of a 30-day old memory increased H3K4me3 and DNA 5hmC levels at a CpG-enriched coding region of c-fos , but not Npas4 , in the anterior cingulate cortex, suggesting that while these two epigenetic mechanisms co-occur following the retrieval of a recent or remote memory, their gene targets differ depending on the brain region. Additionally, we found that in vivo siRNA-mediated knockdown of the H3K4me3 methyltransferase Mll1 in CA1 abolished retrieval-induced increases in DNA 5hmC levels at the Npas4 gene, suggesting that H3K4me3 couples to DNA 5hmC mechanisms. Consistent with this, loss of Mll1 prevented retrieval-induced increases in Npas4 mRNA levels in CA1 and impaired fear memory. Collectively, these findings suggest an important link between histone methylation and DNA hydroxymethylation mechanisms in the epigenetic control of de novo gene transcription triggered by memory retrieval. [ABSTRACT FROM AUTHOR]

Alcohol-use disorder (AUD) is a relapsing disorder associated with excessive ethanol consumption. Recent studies support the involvement of epigenetic mechanisms in the development of AUD. Studies carried out so far have focused on a few specific epigenetic modifications. The goal of this project was to investigate gene expression changes of epigenetic regulators that mediate a broad array of chromatin modifications after chronic alcohol exposure, chronic alcohol exposure followed by 8 h withdrawal, and chronic alcohol exposure followed by 21 days of abstinence in Withdrawal-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) selected mouse lines. We found that chronic vapor exposure to highly intoxicating levels of ethanol alters the expression of several chromatin remodeling genes measured by quantitative PCR array analyses. The identified effects were independent of selected lines, which, however, displayed baseline differences in epigenetic gene expression. We reported dysregulation in the expression of genes involved in histone acetylation, deacetylation, lysine and arginine methylation and ubiquitinationhylation during chronic ethanol exposure and withdrawal, but not after 21 days of abstinence. Ethanol-induced changes are consistent with decreased histone acetylation and with decreased deposition of the permissive ubiquitination mark H2BK120ub, associated with reduced transcription. On the other hand, ethanol-induced changes in the expression of genes involved in histone lysine methylation are consistent with increased transcription. The net result of these modifications on gene expression is likely to depend on the combination of the specific histone tail modifications present at a given time on a given promoter. Since alcohol does not modulate gene expression unidirectionally, it is not surprising that alcohol does not unidirectionally alter chromatin structure toward a closed or open state, as suggested by the results of this study. [ABSTRACT FROM AUTHOR]

The mammalian brain dynamically activates or silences gene programs in response to environmental input and developmental cues. This neuroplasticity is controlled by signaling pathways that modify the activity, localization, and/or expression of transcriptional-regulatory enzymes in combination with alterations in chromatin structure in the nucleus. Consistent with this key neurobiological role, disruptions in the fine-tuning of epigenetic and transcriptional regulation have emerged as a recurrent theme in studies of the genetics of neurodevelopmental and neuropsychiatric disorders. Furthermore, environmental factors have been implicated in the increased risk of heterogeneous, multifactorial, neuropsychiatric disorders via epigenetic mechanisms. Aberrant epigenetic regulation of gene expression thus provides an attractive unifying model for understanding the complex risk architecture of mental illness. Here, we review emerging genetic evidence implicating dysregulation of histone lysine methylation in neuropsychiatric disease and outline advancements in small-molecule probes targeting this chromatin modification. The emerging field of neuroepigenetic research is poised to provide insight into the biochemical basis of genetic risk for diverse neuropsychiatric disorders and to develop the highly selective chemical tools and imaging agents necessary to dissect dynamic transcriptional-regulatory mechanisms in the nervous system. On the basis of these findings, continued advances may lead to the validation of novel, disease-modifying therapeutic targets for a range of disorders with aberrant chromatin-mediated neuroplasticity. [ABSTRACT FROM AUTHOR]

Developmental proceedings and maintenance of cellular homeostasis are regulated by the precise orchestration of a series of epigenetic events that eventually control gene expression. DNA methylation and post-translational modifications (PTMs) of histones are well-characterized epigenetic events responsible for fine-tuning gene expression. PTMs of histones bear molecular logic of gene expression at chromosomal territory and have become a fascinating field of epigenetics. Nowadays, reversible methylation on histone arginine and lysine is gaining increasing attention as a significant PTM related to reorganizing local nucleosomal structure, chromatin dynamics, and transcriptional regulation. It is now well-accepted and reported that histone marks play crucial roles in colon cancer initiation and progression by encouraging abnormal epigenomic reprogramming. It is becoming increasingly clear that multiple PTM marks at the N-terminal tails of the core histones cross-talk with one another to intricately regulate DNA-templated biological processes such as replication, transcription, recombination, and damage repair in several malignancies, including colon cancer. These functional cross-talks provide an additional layer of message, which spatiotemporally fine-tunes the overall gene expression regulation. Nowadays, it is evident that several PTMs instigate colon cancer development. How colon cancer-specific PTM patterns or codes are generated and how they affect downstream molecular events are uncovered to some extent. Future studies would address more about epigenetic communication, and the relationship between histone modification marks to define cellular functions in depth. This chapter will comprehensively highlight the importance of histone arginine and lysine-based methylation modifications and their functional cross-talk with other histone marks from the perspective of colon cancer development., (Copyright © 2023 Elsevier Inc. All rights reserved.)