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PubMed2005

A Requirement for the Saccharomyces cerevisiae Paf1 complex in snoRNA 3' end formation.

RNA synthesis and processing are coordinated by proteins that associate with RNA polymerase II (pol II) during transcription elongation. The yeast Paf1 complex interacts with RNA pol II and mediates histone modifications during elongation. To elucidate the functions of this complex, we isolated missense mutations in the gene encoding the Rtf1 subunit and used them to identify functionally interacting proteins. We identified NAB3 as a dosage suppressor of rtf1. Nab3, together with Nrd1, directs 3' end formation of nonpolyadenylated RNA pol II transcripts, such as snoRNAs. Deletion of Paf1, but not the Set1, Set2, or Dot1 histone methyltransferases, causes accumulation of snoRNA transcripts that are extended at their 3' ends. The Paf1 complex associates with and facilitates Nrd1 recruitment to the SNR47 gene, suggesting a direct involvement in 3' end formation. Our results reveal a posttranscriptional function for the Paf1 complex, which appears unrelated to its role in histone methylation.

Gene Expression Regulation↗
PubMed2006

SmyD1, a histone methyltransferase, is required for myofibril organization and muscle contraction in zebrafish embryos.

Histone modification has emerged as a fundamental mechanism for control of gene expression and cell differentiation. Recent studies suggest that SmyD1, a novo SET domain-containing protein, may play a critical role in cardiac muscle differentiation. However, its role in skeletal muscle development and its mechanism of actions remains elusive. Here we report that SmyD1a and SmyD1b, generated by alternative splicing of SmyD1 gene, are histone methyltransferases that play a key role in skeletal and cardiac muscle contraction. SmyD1a and SmyD1b are specifically expressed in skeletal and cardiac muscles of zebrafish embryos. Knockdown of SmyD1a and SmyD1b expression by morpholino antisense oligos resulted in malfunction of skeletal and cardiac muscles. The SmyD1 morphant embryos (embryos injected with morpholino oligos) could not swim and had no heartbeat. Myofibril organization in the morphant embryos was severely disrupted. The affected myofibers appeared as immature fibers with centrally located nuclei. Together, these data indicate that SmyD1a and SmyD1b are histone methyltransferases and play a critical role in myofibril organization during myofiber maturation.

Alternative Splicing↗
PubMed2002

Epigenomics and epigenetic therapy of cancer.

Epigenetic inactivation of genes that are crucial for the control of normal cell growth is a hallmark of cancer cells. These epigenetic mechanisms include crosstalk between DNA methylation, histone modification and other components of chromatin higher-order structure, and lead to the regulation of gene transcription. Re-expression of genes epigenetically inactivated can result in the suppression of tumour growth or sensitization to other anticancer therapies. Small molecules that reverse epigenetic inactivation are now undergoing clinical trials in cancer patients. This, together with epigenomic analysis of chromatin alterations such as DNA methylation and histone acetylation, opens up the potential both to define epigenetic patterns of gene inactivation in tumours and to use drugs that target epigenetic silencing.

Chromatin↗
PubMed2004

Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome.

Heterochromatin is defined classically by condensation throughout the cell cycle, replication in late S phase and gene inactivity. Facultative heterochromatin is of particular interest, because its formation is developmentally regulated as a result of cellular differentiation. The most extensive example of facultative heterochromatin is the mammalian inactive X chromosome (Xi). A variety of histone variants and covalent histone modifications have been implicated in defining the organization of the Xi heterochromatic state, and the features of Xi heterochromatin have been widely interpreted as reflecting a redundant system of gene silencing. However, here we demonstrate that the human Xi is packaged into at least two nonoverlapping heterochromatin types, each characterized by specific Xi features: one defined by the presence of Xi-specific transcript RNA, the histone variant macroH2A, and histone H3 trimethylated at lysine 27 and the other defined by H3 trimethylated at lysine 9, heterochromatin protein 1, and histone H4 trimethylated at lysine 20. Furthermore, regions of the Xi packaged in different heterochromatin types are characterized by different patterns of replication in late S phase. The arrangement of facultative heterochromatin into spatially and temporally distinct domains has implications for both the establishment and maintenance of the Xi and adds a previously unsuspected degree of epigenetic complexity.

Cell Line↗
PubMed2005

MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression.

Rett syndrome (RS) is a severe and progressive neurodevelopmental disorder caused by heterozygous mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. MeCP2 is a nuclear protein that binds specifically to methylated DNA and functions as a general transcription repressor in the context of chromatin remodeling complexes. RS shares clinical features with those of Angelman syndrome (AS), an imprinting neurodevelopmental disorder. In AS patients, the maternally expressed copy of UBE3A that codes for the ubiquitin protein ligase 3A (E6-AP) is repressed. The similar phenotype of these two syndromes led us to hypothesize that part of the RS phenotype is due to MeCP2-associated silencing of UBE3A. Indeed, UBE3A mRNA and protein are shown here to be significantly reduced in human and mouse MECP2 deficient brains. This reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA. In addition, MeCP2 deficiency resulted in elevated histone H3 acetylation and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center, with no effect on DNA methylation or SNRPN expression. We conclude, therefore, that MeCP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications result in loss of imprinting of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level and, consequently reduction in UBE3A production.

Angelman Syndrome↗
PubMed2006

RSC mobilizes nucleosomes to improve accessibility of repair machinery to the damaged chromatin.

Repair of DNA double-strand breaks (DSBs) protects cells and organisms, as well as their genome integrity. Since DSB repair occurs in the context of chromatin, chromatin must be modified to prevent it from inhibiting DSB repair. Evidence supports the role of histone modifications and ATP-dependent chromatin remodeling in repair and signaling of chromosome DSBs. The key questions are, then, what the nature of chromatin altered by DSBs is and how remodeling of chromatin facilitates DSB repair. Here we report a chromatin alteration caused by a single HO endonuclease-generated DSB at the Saccharomyces cerevisiae MAT locus. The break induces rapid nucleosome migration to form histone-free DNA of a few hundred base pairs immediately adjacent to the break. The DSB-induced nucleosome repositioning appears independent of end processing, since it still occurs when the 5'-to-3' degradation of the DNA end is markedly reduced. The tetracycline-controlled depletion of Sth1, the ATPase of RSC, or deletion of RSC2 severely reduces chromatin remodeling and loading of Mre11 and Yku proteins at the DSB. Depletion of Sth1 also reduces phosphorylation of H2A, processing, and joining of DSBs. We propose that RSC-mediated chromatin remodeling at the DSB prepares chromatin to allow repair machinery to access the break and is vital for efficient DSB repair.

Chromatin↗
PubMed2005

Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation.

Linker histone H1 plays an important role in chromatin folding in vitro. To study the role of H1 in vivo, mouse embryonic stem cells null for three H1 genes were derived and were found to have 50% of the normal level of H1. H1 depletion caused dramatic chromatin structure changes, including decreased global nucleosome spacing, reduced local chromatin compaction, and decreases in certain core histone modifications. Surprisingly, however, microarray analysis revealed that expression of only a small number of genes is affected. Many of the affected genes are imprinted or are on the X chromosome and are therefore normally regulated by DNA methylation. Although global DNA methylation is not changed, methylation of specific CpGs within the regulatory regions of some of the H1 regulated genes is reduced. These results indicate that linker histones can participate in epigenetic regulation of gene expression by contributing to the maintenance or establishment of specific DNA methylation patterns.

Animals↗
PubMed2004

Regulation of heterochromatin by histone methylation and small RNAs.

Heterochromatin mediates various nuclear processes including centromere function, gene silencing and nuclear organization. Although it was discovered nearly 75 years ago, the pathways involved in heterochromatin establishment, assembly and epigenetic maintenance have been elusive. Recent reports have demonstrated that distinct and novel chromatin-associated factors, including DNA, RNA and histone modifications, are involved in each of these events. These new findings define a novel conserved mechanism of heterochromatin formation that is likely to have an impact on all eukaryotic silencing pathways.

Animals↗
PubMed2006

gammaH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes.

Higher-order chromatin structure presents a barrier to the recognition and repair of DNA lesions. Thus, cells must be equipped with mechanisms to surpass this natural obstacle. DNA damage induces histone H2AX phosphorylation by the phosphoinositide 3-kinase like kinases ATM, ATR and DNA-PKcs. H2AX phosphorylation contributes to DNA double-strand break repair but the mechanisms involved are not yet fully understood. In this review, we discuss recent advances in our understanding of how cells use the epigenetic mark of H2AX phosphorylation to dynamically link the DNA-damage-response machinery to broken chromosomes. In addition, we highlight potential regulatory mechanisms of H2AX phosphorylation and speculate about a central functional role of this post-translational histone modification at the interface of DNA repair, chromatin-structure modulation and cell-cycle checkpoint activation.

Adaptor Proteins, Signal Transducing↗
PubMed2004

A novel protein-DNA interaction involved with the CpG dinucleotide at -30 upstream is linked to the DNA methylation mediated transcription silencing of the MAGE-A1 gene.

To understand the DNA-methylation mediated gene silencing mechanisms, we analyzed in cell culture of the promoter function of the MAGE-A1 gene, which is frequently demethylated and over-expressed in human hepatocellular carcinoma. We have established the correlation of the DNA methylation of the promoter CpG island with expression status of this gene in a panel of the established liver cancer cell lines. The crucial CpG dinucleotide(s) within the minimal promoter subjected to the control mediated by DNA methylation with profound biological functions was also delineated. Furthermore, a novel sequence-specific DNA-protein interaction at the -30 CpG dinucleotide upstream of the gene was found having a vital part to play in the DNA methylation mediated transcription silencing of the MAGE-A1 gene. Our results would not only provide new insights into the DNA methylation mediated mechanisms over transcription of the MAGE-A1 gene, but also pave the way for further defining the cross-talk among DNA methylation, histone modification and chromatin remodeling in detail.

Antigens, Neoplasm↗
PubMed2002

DNA methylation and chromatin - unraveling the tangled web.

Methylation of cytosines within the CpG dinucleotide by DNA methyltransferases is involved in regulating transcription and chromatin structure, controlling the spread of parasitic elements, maintaining genome stability in the face of vast amounts of repetitive DNA, and X chromosome inactivation. Cellular DNA methylation is highly compartmentalized over the mammalian genome and this compartmentalization is essential for embryonic development. When the complicated mechanisms that control which DNA sequences become methylated go awry, a number of inherited genetic diseases and cancer may result. Much new information has recently come to light regarding how cellular DNA methylation patterns may be established during development and maintained in somatic cells. Emerging evidence indicates that various chromatin states such as histone modifications (acetylation and methylation) and nucleosome positioning (modulated by ATP-dependent chromatin remodeling machines) determine DNA methylation patterning. Additionally, various regulatory factors interacting with the DNA methyltransferases may direct them to specific DNA sequences, regulate their enzymatic activity, and allow their use as transcriptional repressors. Continued studies of the connections between DNA methylation and chromatin structure and the DNA methyltransferase-associated proteins, will likely reveal that many, if not all, epigenetic modifications of the genome are directly connected. Such studies should also yield new insights into treating diseases involving aberrant DNA methylation.

Acetylation↗
PubMed2006

Mechanisms of disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome characterized by tumors of the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands, as well as by neuroendocrine carcinoid tumors, often at a young age. Causal to the syndrome are germline mutations of the MEN1 tumor-suppressor gene. Identification of gene-mutation carriers has enabled presymptomatic diagnosis and treatment of MEN1-related lesions. The product of the MEN1 gene is the nuclear protein menin. Recent observations indicate several functions for menin in the regulation of transcription, serving either as a repressor or as an activator: menin interacts with the activator-protein-1-family transcription factor JunD, changing it from an oncoprotein into a tumor-suppressor protein, putatively by recruitment of histone deacetylase complexes; menin maintains transforming growth factor beta mediated signal transduction involved in parathyroid hormone and prolactin gene expression; and menin is an integral component of histone methyltransferase complexes. In this capacity menin is a regulator of expression of the cyclin-dependent-kinase inhibitors p18INK4C and p27Kip1; furthermore, menin serves as a co-activator of estrogen receptor mediated transcription, by recruiting methyltransferase activity to lysine 4 of histone 3 at the estrogen responsive TFF1(pS2) gene promoter. We propose that menin links transcription-factor function to histone-modification pathways and that this is crucial for MEN1 tumorigenesis. Understanding the molecular pathology of MEN1 tumorigenesis will lead to new therapeutic strategies.

Animals↗
PubMed1999

The homeodomain protein NK-3 recruits Groucho and a histone deacetylase complex to repress transcription.

Transcriptional repression by sequence-specific DNA binding factors is mediated by the recruitment of a corepressor complex to the promoter region. The NK-3 homeodomain protein is a transcriptional repressor that recruits the nuclear protein kinase, homeodomain interacting protein kinase 2 (HIPK2). Here we show that HIPK2 is a component of a corepressor complex containing Groucho and a histone deacetylase complex. Groucho, like HIPK2, acts as a corepressor for NK-3 and binds to NK-3 and HIPK2. Moreover, HIPK2 appears to regulate the corepressor activity of Groucho. Transcriptional repression by NK-3 and Groucho is relieved by the histone deacetylase inhibitor trichostatin A, and both NK-3 and Groucho directly interact with the histone deacetylase HDAC1 that is associated with mSin3A in vivo. Recruitment of the histone deacetylase complex by NK-3 decreases the acetylated histones that are associated with the target gene promoter. These results indicate that NK-3 represses transcription by recruiting a complex containing Groucho and a histone deacetylase complex that leads to histone modification on chromatin and suggest that HIPK2 may play a regulatory role in the corepressor complex formation.

Base Sequence↗
PubMed2005

Vitamin A status in mice affects the histone code of the phosphoenolpyruvate carboxykinase gene in liver.

Vitamin A deficiency decreases hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene expression in mice, and expression is restored with retinoic acid (RA) treatment in vivo. In the studies reported here, we examined changes in histone modification and coregulator association with the regulatory domains of the PEPCK gene in response to alterations in vitamin A status. We identified nuclear receptors that bind to retinoic acid response elements (RAREs) in the PEPCK promoter by electrophoretic mobility shift assay and verified these in vivo using chromatin immunoprecipitation in mouse liver. Hypothetically, nuclear receptors at PEPCK RAREs recruit specific coactivator molecules that contribute to the acetylation of core histones and/or serve as bridging molecules between nuclear receptors and basal transcription factors at the transcription start site. We identified 3 coactivator molecules, cAMP-response element binding protein (CBP), steroid receptor coactivator (SRC)-1, and peroxisome-proliferator activated receptor (PPAR)-gamma-coactivator (PGC)-1alpha, that bound in association with the PEPCK RAREs in vivo. Furthermore, there was differential binding of these coactivators in vitamin A-deficient mice. Related to this, specific lysine residues were acetylated on histones H3 and H4 at the 3 RAREs of the PEPCK promoter, consistent with the action of the above coactivators, and acetylation of certain lysines was significantly decreased with vitamin A deficiency. These results demonstrate the associated changes that occur in nuclear receptor binding, coactivator recruitment, and histone acetylation in response to vitamin A status, identified at specific RAREs in the PEPCK gene in vivo.

Animals↗
PubMed1981

Low-level binding of halothane metabolites to rat liver histones in vivo.

Binding of halothane metabolites to rat liver histones was investigated after in vivo administration of 14C-halothane. Animals were injected with either a mixture of triiodothyronine, glucagon and heparin (TGH) to stimulate liver growth or with saline as a control. Twenty-four hours later, animals were administered 14C-halothane and maintained at 8--10 per cent O2 for 6 hours. Detergent washed nuclei from liver homogenates were subfractionated to allow quantitative measurements of 14C-halothane binding to histones. Although our studies suggest that much of the previously reported binding of halothane metabolites to major cell fractions was a result of redistribution of endoplasmic reticulum components during isolation procedures, carefully controlled experiments demonstrated that the radioactivity associated with histones could not be due to residual microsomal lipid. Of the initial 132 mumol of 14C-halothane administered, 1.1 mumol remained as nonvolatile metabolites in the liver homogenate and 25 pmol were associated with purified histones. This corresponds to approximately one halothane moiety per 15,000 histone molecules. No significant binding to liver cell RNA or DNA was observed. With this low level of histone modification and lack of convincing evidence of halothane metabolite binding to hepatic DNA or RNA, it is unlikely that significant alteration of the genome occurs after exposure to halothane.

Alkylating Agents↗
PubMed2026

m6A RNA modification and its emerging roles in diseases: recent advances and therapeutic implications.

BACKGROUND: In the recent past, insights in post transcriptional regulation of gene expression have profoundly reshaped our understanding of the molecular mechanisms underlying health and disease. This paradigm shift largely stems from the emerging field of epitranscriptomics, which highlights the pivotal role of chemical RNA modifications. While more than 170 distinct chemical modifications on the RNA are known, the m6A modification is the most abundant internal mRNA modification in higher eukaryotic cells, present not only on protein coding transcripts but also on non-coding RNAs, regulated by “writers”, “erasers”, and “readers” that together modulate alternative splicing, nuclear export, translation efficiency, and mRNA stability. MAIN BODY: This review addresses an important gap by presenting a multilayered regulatory framework that catalogs the full repertoire of m6A machinery and uniquely reveals how non-coding RNAs, transcription factors, histone modifications, and chromatin remodelers governs the spatiotemporal specificity of m6A modification. We explore how dysregulation of m6A modification and its regulatory proteins contribute to the development and progression of various diseases such as cardiovascular disease, neurological disorders, cancer, and type 2 diabetes through context-dependent modulation of gene networks. Furthermore, we present an integrative overview of the therapeutic pipeline, tracing the development of small-molecule inhibitors targeting m6A regulators, thus bridging a crucial link between fundamental mechanisms and new therapies. CONCLUSIONS: Overall, this review integrates current findings and emerging insights to provide a comprehensive understanding of m6A biology. By linking upstream regulatory mechanisms with downstream pathological consequences and therapeutic interventions, we highlight the potential of targeting the epitranscriptome for clinical applications.

Humans↗
PubMed2005

Arabidopsis epigenetics: when RNA meets chromatin.

Recent work in plants and other eukaryotes has uncovered a major role for RNA interference in silent chromatin formation. The heritability of the silent state through multiple cell division cycles and, in some instances, through meiosis is assured by epigenetic marks. In plants, transposable elements and transgenes provide striking examples of the stable inheritance of repressed states, and are characterized by dense DNA methylation and heterochromatin histone modifications. Arabidopsis is a useful higher eukaryotes model with which to explore the crossroads between silent chromatin and RNA interference both during development and in the genome-wide control of repeat elements.

Arabidopsis↗
PubMed2005

Epigenetic control of replication origins.

Efficient duplication of the eukaryotic genome requires the spatial and temporal coordination of numerous replication origins on each chromosome. Epigenetic factors, like chromatin environment, can have profound effects on origin site selection, utilization frequency, and cell cycle firing time. Precisely how chromatin contributes to origin site selection and timing is not completely understood. Recently, we reported on the cell cycle changes in chromatin structure at the plasmid replication origins of Epstein-Barr Virus (EBV) and Kaposi's Sarcoma-Associated Herpes virus (KSHV). These studies and others suggest that cell cycle changes in histone modification and nucleosome remodeling regulate prereplication factor assembly and initiation of DNA replication at origins. We discuss how these studies of viral origins may provide important insights into epigenetic control of cellular chromosome origins.

Epigenesis, Genetic↗