Histone modification patterns associated with the human X chromosome

Brinkman, Arie B.; Roelofsen, Thijs; Pennings, Sebastiaan W C; Martens, Joost H.A.; Jenuwein, Thomas; Stunnenberg, Hendrik G.

doi:10.1038/sj.embor.7400686

Cited by 97 publications

(90 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A similar study on cancer genes suggested that histone modifications of demethylated genes do not fully recover to euchromatic states [47]. Interestingly, recent findings have shown that H3K9me3 is associated with active genes [48][49] and is dynamically present in active transcribed regions together with heterochromatin protein, HP1γ [50], suggesting the role of H3K9me3 in 5azadC-induced gene activation. Thus, gene activation by 5azadC seems to be more complex than the authentic model of epigenetic gene activation and silencing.…”

Section: Discussionmentioning

confidence: 95%

Resistance to 5-aza-2'-deoxycytidine in Genic Regions Compared to Non-genic Repetitive Sequences

et al. 2010

View full text Add to dashboard Cite

Abstract. The DNA methyltransferase (Dnmt) inhibitor and demethylating agent 5-aza-2'-deoxycytidine (5azadC) has been used to induce cellular differentiation and gene activation. It has been approved for treating several kinds of malignancies due to its ability to reactivate silenced tumor suppressor genes. Considering the potential effect of 5azadC on non-targeted genomic regions in normal cells, we investigated its effect on repetitive sequences and selected gene loci, Sall3, Per1, Clu, Dpep1 and Igf2r, including tissue-dependent and differentially methylated regions, by treating mouse NIH/3T3 fibroblast cells with concentrations of 5azadC ranging from 0.001 to 5 μM. Demethylation of minor satellite repeats and endogenous viruses was concentration dependent, and the demethylation was strong at 1 and 5 μM. In genic regions, the methylation level decreased only at 0.1 μM, but was minimally altered at concentrations lower or higher, regardless of the abundance of CpG sites. Thus, repeats are strongly demethylated, but genic regions are only demethylated at effective doses. Genes were activated by 5azadC treatment and were accompanied by a unique combination of histone modifications in genic regions, including an increased level of H3K9me3 and a decreased level of AcH3. Increase of H3K9me3 in genic regions was not observed in Dnmt knock out cells. We identified differential effects of 5azadC on repetitive sequences and genic regions and revealed the importance of choosing appropriate 5azadC doses to achieve targeted gene recovery. Key words: 5-aza-2'-deoxycytidine, Decitabine, DNA methylation, Epigenetics, Histone modification (J. Reprod. Dev. 56: [86][87][88][89][90][91][92][93] 2010) NA methylation is one of the epigenetic events associated with gene regulation and function. Hypermethylation of promoter regions of tumor suppressor genes causes silencing of the genes that lead to cancer [1][2][3]. Thus, reversing the methylation status of gene promoters to their prevalent methylation states has become a treatment option for certain cancer types. To date, there are many types of demethylating agents that have been shown to inhibit promoter methylation and reactivate silenced genes [4][5][6]. Some of these have been approved or are in clinical studies to be developed as cancer drugs [7].The cytosine analog 5-aza-2'-deoxycytidine (5azadC), also known as decitabine, has been widely used as a DNA methyltransferase (Dnmt) inhibitor to reverse aberrant hypermethylation [8,9]. It has been approved for hematological malignancies, showing favorable results with low dose treatment [10,11]. Known to have dual modes of action, 5azadC at low doses induces gene hypomethylation, whereas high doses of 5azadC induce cytotoxicity and cause severe side effects in patients [12,13].Nearly 40% of the mouse genome is composed of repetitive sequences including different classes of interspersed repeats, such as LINEs, SINEs, LTR elements and satellites, that are mainly found in heterochromatin regions [14]. Most repeats are densely m...

show abstract

Section: Discussionmentioning

confidence: 95%

Resistance to 5-aza-2'-deoxycytidine in Genic Regions Compared to Non-genic Repetitive Sequences

et al. 2010

View full text Add to dashboard Cite

show abstract

“…In contrast, others have found that H3me3K9 associates with promoters that are bound by the RNA polymerase II complex [8] or with actively transcribed genes [17,19,26]. For example, one study found high levels of H3me3K9 over the highly transcribed gamma globin locus [26] and a second study found that H3me3K9 was localized to the coding region of several active genes [17]. Clearly, a comprehensive comparison of H3me3K9 and H3me3K27 binding sites in human cells is needed to provide insight into the relative roles of these two modifications in gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…Perhaps the best examples for association of transcriptional repression of an endogenous gene with the presence of H3me3K9 comes from an analysis of the POU5F1 promoter during differentiation [20] and of ASCL2 after knockdown of a Jumonji family member [13]. In contrast, others have found that H3me3K9 associates with promoters that are bound by the RNA polymerase II complex [8] or with actively transcribed genes [17,19,26]. For example, one study found high levels of H3me3K9 over the highly transcribed gamma globin locus [26] and a second study found that H3me3K9 was localized to the coding region of several active genes [17].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genome-Wide Analysis of KAP1 Binding Suggests Autoregulation of KRAB-ZNFs

O’Geen¹,

Squazzo²,

Iyengar³

et al. 2005

PLoS Genet

View full text Add to dashboard Cite

We performed a genome-scale chromatin immunoprecipitation (ChIP)-chip comparison of two modifications (trimethylation of lysine 9 [H3me3K9] and trimethylation of lysine 27 [H3me3K27]) of histone H3 in Ntera2 testicular carcinoma cells and in three different anatomical sources of primary human fibroblasts. We found that in each of the cell types the two modifications were differentially enriched at the promoters of the two largest classes of transcription factors. Specifically, zinc finger (ZNF) genes were bound by H3me3K9 and homeobox genes were bound by H3me3K27. We have previously shown that the Polycomb repressive complex 2 is responsible for mediating trimethylation of lysine 27 of histone H3 in human cancer cells. In contrast, there is little overlap between H3me3K9 targets and components of the Polycomb repressive complex 2, suggesting that a different histone methyltransferase is responsible for the H3me3K9 modification. Previous studies have shown that SETDB1 can trimethylate H3 on lysine 9, using in vitro or artificial tethering assays. SETDB1 is thought to be recruited to chromatin by complexes containing the KAP1 corepressor. To determine if a KAP1-containing complex mediates trimethylation of the identified H3me3K9 targets, we performed ChIP-chip assays and identified KAP1 target genes using human 5-kb promoter arrays. We found that a large number of genes of ZNF transcription factors were bound by both KAP1 and H3me3K9 in normal and cancer cells. To expand our studies of KAP1, we next performed a complete genomic analysis of KAP1 binding using a 38-array tiling set, identifying ;7,000 KAP1 binding sites. The identified KAP1 targets were highly enriched for C 2 H 2 ZNFs, especially those containing Krü ppel-associated box (KRAB) domains. Interestingly, although most KAP1 binding sites were within core promoter regions, the binding sites near ZNF genes were greatly enriched within transcribed regions of the target genes. Because KAP1 is recruited to the DNA via interaction with KRAB-ZNF proteins, we suggest that expression of KRAB-ZNF genes may be controlled via an auto-regulatory mechanism involving KAP1.

show abstract

“…Even within the same lysine residue, the biological consequences of methylation seem to be variable. For example, methylation of histone H3 lysine 9 (H3K9), long considered a hallmark of heterochromatin (2)(3)(4)(5)(6)(7)(8), was recently found to also be present at the transcribed regions of active mammalian genes (9,10), suggesting that certain methyl marks can have multiple functions in the cell.…”

mentioning

confidence: 99%

Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis

Shi

Sun

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

230

219

View full text Add to dashboard Cite

It is well-documented that the methylation of histone H3 lysine 4 (H3K4) and of H3K9 are mutually exclusive, an epigenetic phenomenon conserved from yeast to humans. How this opposed methylation modification is accomplished and coordinated in mammalian cells is poorly understood. Here we report that the H3K9 trimethyl demethylase JMJD2B is an integral component of the H3K4-specific methyltransferase, the mixed-lineage leukemia (MLL) 2 complex. We show that the JMJD2B/MLL2 complex is copurified with estrogen receptor α (ERα) and is required for ERα-regulated transcription. We demonstrate that H3K9 demethylation and H3K4 methylation are coordinated in ERα-activated transcription such that H3K9 demethylation is a prerequisite for H3K4 methylation. Significantly, depletion of JMJD2B impairs the estrogen-induced G 1 /S transition of the cell cycle in vitro and inhibits breast tumorigenesis in vivo. Interestingly, JMJD2B itself is an ERα target gene, and forms a feed-forward regulatory loop in regulation of the hormone response. Our results provide a molecular basis for the coordinated H3K4 methylation/H3K9 demethylation in transcription activation, link the trimethyl demethylase JMJD2B to euchromatin functions, and provide a mechanism for JMJD2B in breast carcinogenesis.histone methylation | breast cancer R ecent studies indicate that, analogous to other covalent histone modifications such as acetylation, histone methylation is reversible. However, in contrast to histone acetylation, which is generally associated with active transcription, histone methylation can be associated with either activation or repression of transcription, depending on what effector protein is recruited (1). Even within the same lysine residue, the biological consequences of methylation seem to be variable. For example, methylation of histone H3 lysine 9 (H3K9), long considered a hallmark of heterochromatin (2-8), was recently found to also be present at the transcribed regions of active mammalian genes (9, 10), suggesting that certain methyl marks can have multiple functions in the cell.Given the complexity of histone methylation modification, the integration and/or coordination of methylation/demethylation in a particular biological process becomes an issue of great importance in further understanding the role of histone methylation in nucleosome functioning. Specifically, actively transcribed genes, including the ones that are regulated by estrogen receptor (ER) (11-13), are marked by methylation at histone H3K4, but at the same time by demethylation at H3K9; H3K4 and H3K9 methylation levels are mutually exclusive, and this relationship is conserved from fission yeast to humans. How opposed H3K4 methylation and H3K9 demethylation are achieved and coordinated in transcription activation in mammalian cells is not fully understood.H3K4 methylation is deposited by a family of histone methyltransferases (HMT) that share a conserved SET (Su(var), E(z), and Trithorax) domain. In mammalian cells, multiple HMTs have been characterized: SET1A and SE...

show abstract

Histone modification patterns associated with the human X chromosome

Cited by 97 publications

References 27 publications

Resistance to 5-aza-2'-deoxycytidine in Genic Regions Compared to Non-genic Repetitive Sequences

Resistance to 5-aza-2'-deoxycytidine in Genic Regions Compared to Non-genic Repetitive Sequences

Genome-Wide Analysis of KAP1 Binding Suggests Autoregulation of KRAB-ZNFs

Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis

Contact Info

Product

Resources

About