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PubMed2002

Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression.

Histone deacetylases (HDACs) modulate chromatin structure and transcription, but little is known about their function in mammalian development. HDAC1 was implicated previously in the repression of genes required for cell proliferation and differentiation. Here we show that targeted disruption of both HDAC1 alleles results in embryonic lethality before E10.5 due to severe proliferation defects and retardation in development. HDAC1-deficient embryonic stem cells show reduced proliferation rates, which correlate with decreased cyclin-associated kinase activities and elevated levels of the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1). Similarly, expression of p21 and p27 is up-regulated in HDAC1-null embryos. In addition, loss of HDAC1 leads to significantly reduced overall deacetylase activity, hyperacetylation of a subset of histones H3 and H4 and concomitant changes in other histone modifications. The expression of HDAC2 and HDAC3 is induced in HDAC1-deficient cells, but cannot compensate for loss of the enzyme, suggesting a unique function for HDAC1. Our study provides the first evidence that a histone deacetylase is essential for unrestricted cell proliferation by repressing the expression of selective cell cycle inhibitors.

Alleles↗
PubMed2003

The c-myc insulator element and matrix attachment regions define the c-myc chromosomal domain.

Insulator elements and matrix attachment regions are essential for the organization of genetic information within the nucleus. By comparing the pattern of histone modifications at the mouse and human c-myc alleles, we identified an evolutionarily conserved boundary at which the c-myc transcription unit is separated from the flanking condensed chromatin enriched in lysine 9-methylated histone H3. This region harbors the c-myc insulator element (MINE), which contains at least two physically separable, functional activities: enhancer-blocking activity and barrier activity. The enhancer-blocking activity is mediated by CTCF. Chromatin immunoprecipitation assays demonstrate that CTCF is constitutively bound at the insulator and at the promoter region independent of the transcriptional status of c-myc. This result supports an architectural role of CTCF rather than a regulatory role in transcription. An additional higher-order nuclear organization of the c-myc locus is provided by matrix attachment regions (MARs) that define a domain larger than 160 kb. The MARs of the c-myc domain do not act to prevent the association of flanking regions with lysine 9-methylated histones, suggesting that they do not function as barrier elements.

Animals↗
PubMed2026

Handle with care: packaging the oocyte epigenome for the next generation.

During oocyte growth, substantial epigenetic programming occurs to establish a distinctive epigenome including appropriately patterned DNA methylation and histone modifications. Oocyte epigenetic programming must be tightly spatiotemporally regulated to ensure that a wide variety of epigenetic modifiers correctly establish their respective modifications to mediate precise control of gene expression. Furthermore, epigenetic modifications in oocytes include canonical and non-canonical genomic imprints, which are transmitted through meiosis to offspring. Significantly, disruptions in oocyte epigenetic programming can cause aberrant developmental outcomes in the next generation mediated by altered imprinting. Polycomb repressive complex 2 is an important epigenetic modifier that establishes histone 3 lysine 27 trimethylation and non-canonical imprints during mouse oogenesis, which are important for normal offspring development. While it is widely recognised that altered oocyte epigenetic programming can disrupt offspring development, mechanisms controlling maternal epigenetic inheritance remain poorly understood. The possibility remains that non-canonical imprinting exists in humans, although this requires confirmation. This review discusses mouse and human oocyte epigenetic programming including interactions between various epigenetic modifiers and modifications that form the unique oocyte epigenome. Understanding how oocyte epigenetic programming is regulated will be crucial in discerning how changes to the oocyte epigenome can disrupt epigenetic memory and alter developmental outcomes in offspring.

Animals↗
PubMed2005

A histone code in meiosis: the histone kinase, NHK-1, is required for proper chromosomal architecture in Drosophila oocytes.

To promote faithful propagation of the genetic material during sexual reproduction, meiotic chromosomes undergo specialized morphological changes that ensure accurate segregation of homologous chromosomes. The molecular mechanisms that establish the meiotic chromosomal structures are largely unknown. We describe a mutation in a recently identified Histone H2A kinase, nhk-1, in Drosophila that leads to female sterility due to defects in the formation of the meiotic chromosomal structures. The metaphase I arrest and the karyosome, a critical prophase I chromosomal structure, require nucleosomal histone kinase-1 (NHK-1) function. The defects are a result of failure to disassemble the synaptonemal complex and to load condensin onto the mutant chromosomes. Embryos laid by nhk-1-/- mutant females arrest with aberrant polar bodies and mitotic spindles, revealing that mitosis is affected as well. We analyzed the role of Histone H2A phosphorylation with respect to the histone code hypothesis and found that it is required for acetylation of Histone H3 and Histone H4 in meiosis. These studies reveal a critical role for histone modifications in chromosome dynamics in meiosis and mitosis.

Animals↗
PubMed2004

Recent highlights of RNA-polymerase-II-mediated transcription.

Considerable advances into the basis of RNA-polymerase-II-mediated transcriptional regulation have recently emerged. Biochemical, genetic and structural studies have contributed to novel insights into transcription, as well as the functional significance of covalent histone modifications. New details regarding transcription elongation through chromatin have further defined the mechanism behind this action, and identified how chromatin structure may be maintained after RNAP II traverses a nucleosome. ATP-dependent chromatin remodeling complexes, along with histone chaperone complexes, were recently discovered to facilitate histone exchange. In addition, it has become increasingly clear that transcription by RNA polymerase II extends beyond RNA synthesis, towards a more active role in mRNA maturation, surveillance and export to the cytoplasm.

Animals↗
PubMed2002

Crosstalk between CARM1 methylation and CBP acetylation on histone H3.

BACKGROUND: Dynamic changes in the modification pattern of histones, such as acetylation, phosphorylation, methylation, and ubiquitination, are thought to provide a code for the correct regulation of gene expression mostly by affecting chromatin structure and interactions of non-histone regulatory factors with chromatin. Recent studies have suggested the existence of an interplay between histone modifications during transcription. The CBP/p300 acetylase and the CARM1 methyltransferase can positively regulate the expression of estrogen-responsive genes, but the existence of a crosstalk between lysine acetylation and arginine methylation on chromatin has not yet been established in vivo. RESULTS: By following the in vivo pattern of modifications on histone H3, following estrogen stimulation of the pS2 promoter, we show that arginine methylation follows prior acetylation of H3. Within 15 min after estrogen stimulation, CBP is bound to chromatin, and acetylation of K18 takes place. Following these events, K23 is acetylated, CARM1 associates with chromatin, and methylation at R17 takes place. Exogenous expression of CBP is sufficient to drive the association of CARM1 with chromatin and methylation of R17 in vivo, whereas an acetylase-deficient CBP mutant is unable to induce these events. A mechanism for the observed cooperation between acetylation and arginine methylation comes from the finding that acetylation at K18 and K23, but not K14, tethers recombinant CARM1 to the H3 tail and allows it to act as a more efficient arginine methyltransferase. CONCLUSION: These results reveal an ordered and interdependent deposition of acetylation and arginine methylation during estrogen-regulated transcription and provide support for a combinatorial role of histone modifications in gene expression.

Acetylation↗
PubMed1985

Cell cycle variations in ADP-ribosylation of HeLa nuclear proteins.

Changes in ADP-ribosylation of nuclear proteins during the HeLa cell cycle were determined. Portions of synchronized cultures were withdrawn at intervals and cells were permeabilized by resuspension in hypotonic buffer containing detergents. Nuclear proteins were radioactively labeled by incubating samples with [32P]NAD. Modified species were resolved using one-dimensional and two-dimensional polyacrylamide gel electrophoresis. Measurements of the incorporation of [32P]NAD by permeabilized cells showed that ADP-ribosylation is a significant modification throughout the cell cycle. A twofold increase was detected during S phase. Autoradiograms of one-dimensional sodium dodecyl sulfate-polyacrylamide gels revealed that many nuclear nonhistones are modified, though the major acceptors of 32P were the histones and a 116,000-Da species (poly(ADP-ribose) polymerase). The same modified proteins were present through the cell cycle, but densitometry of autoradiograms demonstrated a general increase in the level of incorporation in S phase. Autoradiograms of two-dimensional gels of nuclear proteins labeled with [32P]NAD were consistent with these results. Although nonhistones of isolated metaphase chromosomes show a substantial reduction in ADP-ribosylation, histone modification is essentially unchanged in metaphase.

Adenosine Diphosphate Ribose↗
PubMed2004

Gene silencing by nuclear orphan receptors.

Nuclear orphan receptors represent a large and diverse subgroup in the nuclear receptor superfamily. Although putative ligands for these orphan members remain to be identified, some of these receptors possess intrinsic activating, inhibitory, or dual regulatory functions in development, differentiation, homeostasis, and reproduction. In particular, gene-silencing events elicited by chicken ovalbumin upstream promoter-transcription factors (COUP-TFs); dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1); germ cell nuclear factor (GCNF); short heterodimer partner (SHP); and testicular receptors 2 and 4 (TR2 and TR4) are among the best characterized. These orphan receptors are critical in controlling basal activities or hormonal responsiveness of numerous target genes. They employ multiple and distinct mechanisms to mediate target gene repression. Complex cross-talk exists between these orphan receptors at their cognate DNA binding elements and an array of steroid?nonsteroid hormone receptors, other transcriptional activators, coactivators and corepressors, histone modification enzyme complexes, and components of basal transcriptional components. Therefore, perturbation induced by these orphan receptors at multiple levels, including DNA binding activities, receptor homo- or heterodimerization, recruitment of cofactor proteins, communication with general transcriptional machinery, and changes at histone acetylation status and chromatin structures, may contribute to silencing of target gene expression in a specific promoter or cell-type context. Moreover, the findings derived from gene-targeting studies have demonstrated the significance of these orphan receptors' function in physiologic settings. Thus, COUP-TFs, DAX-1, GCNF, SHP, and TR2 and 4 are known to be required for multiple physiologic and biologic functions, including neurogenesis and development of the heart and vascular system steroidogenesis and sex determination, gametogenesis and embryonic development, and cholesterol?lipid homeostasis.

Animals↗
PubMed2024

DKK1-SE recruits AP1 to activate the target gene DKK1 thereby promoting pancreatic cancer progression.

Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.

Humans↗
PubMed2006

Histone H3 lysine 9 and H4 lysine 20 trimethylation and the expression of Suv4-20h2 and Suv-39h1 histone methyltransferases in hepatocarcinogenesis induced by methyl deficiency in rats.

The field of cancer epigenetics has received much attention in recent years. However, the relationship of cancer epigenetics with cancer etiology is not clear. Recent studies suggest the involvement of altered DNA methylation and histone modifications in the emergence of epigenetically reprogrammed cells with specific tumor-related phenotypes at premalignant stages of tumor development. In this study, we used a methyl-deficient model of rodent hepatocarcinogenesis to examine the roles of DNA, histone H3 lysine 9 and histone H4 lysine 20 methylation, and the level of the expression of Suv39h1 and Suv4-20h2 histone methyltransferases in the carcinogenic process. We demonstrated that the development of liver tumors was characterized by progressive demethylation of DNA repeats, decrease in histone H4 lysine 20 trimethylation, and a gradual decrease in the expression of Suv4-20h2 histone methyltransferase. A prominent increase in the trimethylation of histone H3 lysine 9 and in the expression of Suv39h1 histone methyltransferase was observed in preneoplastic nodules and liver tumors indicating the promotional role of these epigenetic alterations at later stages of carcinogenesis. The appearance of tumor-specific epigenetic alterations (demethylation of repetitive elements, loss of histone H4 lysine 20 trimethylation, altered expression of Suv4-20h2 and Suv39h1 histone methyltransferases) at preneoplastic stages of hepatocarcinogenesis provides experimental support for the epigenetic hypothesis of tumorigenesis that considers stress-induced epigenetic reprogramming of the cell as an important prerequisite to succeeding mutations.

Animals↗
PubMed2006

Role of plant CBP/p300-like genes in the regulation of flowering time.

CREB-binding protein (CBP) and its homolog p300 possess histone acetyltransferase activity and function as key transcriptional co-activators in the regulation of gene expression that controls differentiation and development in animals. However, the role of CBP/p300-like genes in plants has not yet been elucidated. Here, we show that Arabidopsis CBP/p300-like genes promote flowering by affecting the expression of a major floral repressor FLOWERING LOCUS C (FLC). Although animal CBP and p300 generally function as co-activators, Arabidopsis CBP/p300-like proteins are required for the negative regulation of FLC. This CBP/p300-mediated FLC repression may involve reversible protein acetylation independent of histone modification within FLC chromatin.

Arabidopsis↗
PubMed2005

Epigenetic regulation of mammalian pericentric heterochromatin in vivo by HP1.

We developed a model system whereby HP1 can be targeted to pericentric heterochromatin in ES cells lacking Suv(3)9h1/2 histone methyltransferase (HMTase) activities. HP1 so targeted can reconstitute tri-methylated lysine 9 of histone H3 (Me(3)K9H3) and tri-methylated lysine 20 of histone H4 (Me(3)K20H4) at pericentric heterochromatin, indicating that HP1 can regulate the distribution of these histone modifications in vivo. Both homo- and hetero-typic interactions between the HP1 isotypes were demonstrated in vivo as were HP1 interactions with the ESET/SETDB1 HMTase and the ATRX chromatin remodelling enzyme. We conclude that HP1 not only "deciphers" the histone code but can also "encode it".

Animals↗
PubMed2026

Regulation of the histone H3K36 methyltransferase Set2 by the histone chaperone Spt6.

Histone H3 lysine 36 methylation is a conserved histone modification that is critical for maintaining eukaryotic transcriptional fidelity and genomic stability. In Saccharomyces cerevisiae, this modification is catalyzed by Set2, an ortholog of the mammalian H3K36 methyltransferase SETD2. Previous genetic, biochemical, and structural studies showed that Set2 activity is repressed by a Set2 autoinhibitory domain (AID) and that activation requires the direct binding of the histone chaperone Spt6. To study the role of Spt6 and Set2 autoinhibition in vivo, we have isolated and analyzed multiple classes of Spt6 and Set2 mutants. Our results suggest an autoinhibited form of Set2 in which the catalytic domain (CD) is bound by the AID. In strong agreement with our genetic results, biophysical experiments demonstrate that the CD and AID physically interact, and that the autoinhibition mutants disrupt this interaction. Finally, RNA sequencing and chromatin immunoprecipitation and sequencing studies show the importance of the Set2-Spt6 interaction for transcription and H3K36 methylation genome-wide. Taken together, our results support a model in which Set2 exists in an inactive, autoinhibited state in vivo through direct CD-AID interactions, with binding by Spt6 required to release the autoinhibition.

Saccharomyces cerevisiae Proteins↗
PubMed2026

Regulation of the histone H3K36 methyltransferase Set2 by the histone chaperone Spt6.

Histone H3 lysine 36 methylation is a conserved histone modification that is critical for maintaining eukaryotic transcriptional fidelity and genomic stability. In Saccharomyces cerevisiae, this modification is catalyzed by Set2, an ortholog of the mammalian H3K36 methyltransferase SETD2. Previous genetic, biochemical, and structural studies showed that Set2 activity is repressed by a Set2 autoinhibitory domain (AID) and that activation requires the direct binding of the histone chaperone Spt6. To study the role of Spt6 and Set2 autoinhibition in vivo, we have isolated and analyzed multiple classes of Spt6 and Set2 mutants. Our results suggest an autoinhibited form of Set2 in which the catalytic domain is bound by the AID. In strong agreement with our genetic results, biophysical experiments demonstrate that the catalytic domain and AID physically interact, and that the autoinhibition mutants disrupt this interaction. Finally, RNA-seq and ChIP-seq studies show the importance of the Set2-Spt6 interaction for transcription and H3K36 methylation genome-wide. Taken together, our results support a model in which Set2 exists in an inactive, autoinhibited state in vivo through direct catalytic domain-AID interactions, with binding by Spt6 required to release this autoinhibited state.

Journal Article↗
PubMed2005

Tilling the chromatin landscape: emerging methods for the discovery and profiling of protein-DNA interactions.

Interactions between protein and DNA are essential for cellular function. The incremental process of developing global approaches to study chromatin began with the in vitro characterization of chromatin structural components and modifications of the versatile chromatin immunoprecipitation (ChIP) assay, capable of analyzing protein-DNA interactions in vivo. Among the emerging global approaches are ChIP cloning, ChIP display, differential chromatin scanning, ChIP-chip, DamID chromatin profiling, and chromatin array. These methods have been used to assess transcription-factor binding and (or) histone modification. This review describes these global methods and illustrates their potential in answering biological questions.

Acetylation↗
PubMed1993

Dynamics of unfolded nucleosomal fiber.

The "rigidity" of chromatin fiber solenoidal structure in different states of condensation was evaluated with the help of gel-electrophoresis. A new property of the unfolded nucleosomal fiber-the capacity to condense with temperature-was demonstrated. These results together with our previously obtained data (W.A. Krajewski et al., Mol. Gen. Genet. 230, pp. 442-448, 1991; W.A. Krajewski et al., Ibid. 231, pp. 17-22, 1991) testify that changes in DNA linking number of transcriptionally active minichromosomes arise in vivo from alteration of nucleosomal solenoid parameters (i.e. from supernucleosomal level of chromatin organization), rather than from core histone modifications only or from increased flexibility of DNA within nucleosomes.

Animals↗
PubMed2006

Illumination is necessary and sufficient to induce histone acetylation independent of transcriptional activity at the C4-specific phosphoenolpyruvate carboxylase promoter in maize.

Expression of the C4-specific phosphoenolpyruvate carboxylase (C4-PEPC) gene in maize (Zea mays) is regulated in a tissue-specific manner, but affected by light and nutrient availability. We manipulated these stimuli in a combinatorial manner and analyzed concomitant changes in histone acetylation of the nucleosomes associated with the C4-PEPC gene in relation to transcriptional activity and steady-state mRNA levels. Whereas the transition from the lowest activity to an intermediate activity was observed in the absence of histone acetylation, the light-induced boost to full activity was associated with strong enhancement of the acetylation of both histones H3 and H4 limited to the gene region. Once activated by light, prolonged darkness was necessary to reduce both transcription and, in parallel, histone acetylation. Unexpectedly, histone acetylation was also induced in bundle sheath cells, although the transcriptional activity did not respond to illumination in this tissue. Furthermore, we were able to down-regulate the promoter by nitrogen depletion in the light without any decrease in the hyperacetylation of histone H4. When plants kept in prolonged darkness were nitrogen depleted and then exposed to light, transcription was not induced, but the promoter chromatin became hyperacetylated. We suggest a model where inhibition of a histone deacetylase in the light triggers H4 hyperacetylation at the C4-PEPC gene promoter regardless of the transcriptional activity of the gene. Our data indicate that an understanding of the interplay between histone modification and transcription requires analysis of signal integration on promoters in vivo.

Acetylation↗
PubMed2005

Involvement of a short interspersed element in epigenetic transcriptional silencing of the amoebapore gene in Entamoeba histolytica.

Transcriptional silencing of an amoebapore (ap-a) gene occurred in Entamoeba histolytica following the transfection of plasmids containing a DNA segment (473 bp) homologous to the 5' upstream region of the gene (R. Bracha, Y. Nuchamowitz, and D. Mirelman, Eukaryot. Cell 2:295-305, 2003). This segment contains the promoter region of the ap-a gene, a T-rich stretch, followed by a truncated SINE1 (short interspersed element 1) that is transcribed from the antisense strand. Transfection of plasmids containing truncated SINE1 sequences which lack their 3' regulatory elements upstream of the ap-a gene was essential for the downstream silencing of the ap-a gene while transfection with plasmids containing the entire SINE1 sequence or without the T-rich stretch promoted the overexpression of the ap-a gene. Both the T-rich stretch and sequences of the 5' SINE1 were essential for the transcription of SINE1. RNA extracts from gene-silenced cultures showed small amounts of short (approximately 140-nucleotide), single-stranded molecules with homology to SINE1 but no short interfering RNA. Chromatin immunoprecipitation analysis with an antibody against methylated K4 of histone H3 showed a demethylation of K4 at the domain of the ap-a gene, indicating transcriptional inactivation. These results suggest the involvement of SINE1 in triggering the gene silencing and the role of histone modification in its epigenetic maintenance.

Animals↗