Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome

Liang, Gangning; Lin, Joy; Wei, Vivian; Yoo, Christine B.; Cheng, Jonathan; Nguyen, Carvell T.; Weisenberger, Daniel J.; Egger, Gerda; Takai, Daiya; Gonzales, Felicidad A.; Jones, Peter A.

doi:10.1073/pnas.0401866101

Cited by 430 publications

(362 citation statements)

References 23 publications

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“…For genes containing all three markings, we found that modification sites overlapped within 1 kb of the TSS in about 90% of genes. These results are consistent with the previous assignment of H3K9Ac and H3K4Me2 to 0.5 kb of either side of the TSS of expressed genes (Liang et al, 2004). Our single gene ChIP confirmed the tiling array data in revealing robust H3K9Me3 signals among highly expressed genes such as HOXA9, MEIS1 and OTX2 in cells overexpressing these genes.…”

Section: Discussionsupporting

confidence: 92%

Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells

Zheng

Morrison

et al. 2007

Oncogene

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Histone H3 lysine 9 trimethylation (H3K9Me3) has been associated with transcriptional repression, but recent findings implicate this chromatin modification in transcriptional activation and mRNA elongation by RNA polymerase II. Here, we applied immunoprecipitation (IP) with a custom DNA tiling microarray containing many transcription factors important in development and cancer (for example homeotic genes; N ¼ 683 total genes) to explore the relationship between H3K9Me3 and other histone modifications with the differential expression of genes. Cancer cell lines derived from different tissues (2 leukemia, 2 medulloblastoma) were characterized with IP antibodies to H3K9Me3, H3K4 dimethylation (H3K4Me2) and H3K9 acetylation (H3K9Ac). MV4-11 is known to overexpress the HOXA9 and MEIS1 genes, whereas D283 overexpresses the OTX2 homeobox gene. Gene expression was assessed by Affymetrix U133 array. Mapping the number and size of histone markings demonstrated significant colocalization of H3K9Ac and H3K4Me2 with H3K9Me3, indicating a pattern of putative 'activating' and 'repressive' markings. The median site size was 600-821 bp and 72-95% or 53-80% of chromatin signal sites were located within 1 kb or 500 bp of transcription start sites (TSS), respectively. A relatively small number of genes displayed additional H3K9Me3 sites in the 5 0 -region distant from the TSS. Comparing genes with modification sites to those without sites in their promoters confirmed the positive associations of H3K9Ac and H3K4Me2 with gene expression and revealed that H3K9Me3 is associated with active genes rather than being a repressive marking as previously thought. The positive regulatory effect of all three types of modifications were quantitatively correlated with site size, and applied to absolute gene expression within a single cell line as well as relative expression among pairs of cell lines. Extended patterns of H3K9Me3 upstream of some genes (for example HOXA9 and OTX2) may result from the action of multiple promoter elements. We found an inverse relationship between promoter DNA hypermethylation and H3K9Me3 in three studied genes (HOXA9, TMS1, RASSF1A). The localization of H3K9Me3 downstream of the TSSs of expressed genes and not within promoter regions of hypermethylated and silenced genes is consistent with the proposed coupling of H3K9Me3 with RNA polymerase II. Our results indicate a need for revising aspects of the histone code involving H3 lysine methylation. Awareness of H3K9Me3 as a mark of gene activity, not repression, is especially important for the classification of human cancer using chromatin and histone profiles.

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Section: Discussionsupporting

confidence: 92%

Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells

Zheng

Morrison

et al. 2007

Oncogene

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“…24 Figure 3 shows that di-and tri-methylation of lysine 4 of histone H3 (H3-Me2K4 and H3-Me3K4) in PANC1 cells were quite similar to those in BxPC3 cells for ChIP regions 1 to 4. However, in ChIP region 5, H3-Me2K4 and H3-Me3K4 were more highly methylated in BxPC3 cells than in PANC1 cells.…”

Section: Selection Of Msp Primers For Different Regions Of the Muc2 Gmentioning

confidence: 95%

MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer

Yamada

Hamada

Goto

et al. 2006

Intl Journal of Cancer

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Mucins are highly glycosylated proteins that play important roles in carcinogenesis. In pancreatic neoplasia, MUC2 mucin has been demonstrated as a tumor suppressor and we have reported that MUC2 is a favorable prognostic factor. Regulation of MUC2 gene expression is known to be controlled by DNA methylation, but the role of histone modification for MUC2 gene expression has yet to be clarified. Herein, we provide the first report that the histone H3 modification of the MUC2 promoter region regulates MUC2 gene expression. To investigate the histone modification and DNA methylation of the promoter region of the MUC2 gene, we treated 2 human pancreatic cancer cell lines, PANC1 (MUC2-negative) and BxPC3 (MUC2-positive) with the DNA methyltransferase inhibitor 5-azacytidine (5-aza), the histone deacetylase inhibitor trichostatin A (TSA), and a combination of these agents. The DNA methylation level of PANC1 cells was decreased by all 3 treatments, whereas histone H3-K4/K9 methylation and H3-K9/K27 acetylation in PANC1 cells was changed to the level in BxPC3 cells by treatment with TSA alone and with the 5-aza/TSA combination. The expression level of MUC2 mRNA in PANC1 cells exhibited a definite increase when treated with TSA and 5-aza/TSA, whereas 5-aza alone induced only a slight increase. Our results suggest that histone H3 modification in the 5 0 flanking region play an important role in MUC2 gene expression, possibly affecting DNA methylation. An understanding of these intimately correlated epigenetic changes may be of importance for predicting the outcome of patients with pancreatic neoplasms. ' 2006 Wiley-Liss, Inc.

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“…proposal that Set1, the responsible methyltransferase, travels with the elongating RNA polymerase II complex some distance along a gene 13,14 . Dimethylation of H3-K9, which is thought to mediate repression of transcription 15,16 , was detected in antiphase to the acetylation of the same residue (Fig.…”

Section: Jürgen a Ripperger 12 And Ueli Schiblermentioning

confidence: 99%

Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions

2006

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Mammalian circadian rhythms are based on transcriptional and post-translational feedback loops. Essentially, the activity of the transcription factors BMAL1 (also known as MOP3) and CLOCK is rhythmically counterbalanced by Period (PER) and Cryptochrome (CRY) proteins to govern time of day-dependent gene expression 1 . Here we show that circadian regulation of the mouse albumin D element-binding protein (Dbp) gene involves rhythmic binding of BMAL1 and CLOCK and marked daily chromatin transitions. Thus, the Dbp transcription cycle is paralleled by binding of BMAL1 and CLOCK to multiple extra-and intragenic E boxes, acetylation of Lys9 of histone H3, trimethylation of Lys4 of histone H3 and a reduction of histone density. In contrast, the antiphasic daily repression cycle is accompanied by dimethylation of Lys9 of histone H3, the binding of heterochromatin protein 1a and an increase in histone density. The rhythmic conversion of transcriptionally permissive chromatin to facultative heterochromatin relies on the presence of functional BMAL1-CLOCK binding sites.Circadian rhythms are based on cell-autonomous oscillators that maintain gene expression with a period length of about a day even in the absence of external timing cues 2,3 . In mammals, the rhythmgenerating molecular circuitry is thought to rely on the opposing effects of transcriptional activators and repressors that generate a negative feedback loop [1][2][3] . Briefly, the PAS domain helix-loop-helix proteins BMAL1 and CLOCK stimulate transcription of Cry and Per via binding to E-box motifs present in these genes. Once the repressor proteins CRY and PER reach a critical concentration, they form complexes with the CLOCK-BMAL heterodimer and thereby attenuate the transactivation potential of these transcription factors. As a consequence, Per and Cry transcription is reduced, PER and CRY accumulation decreases below the concentration required for autorepression and a new transcription cycle of PER and CRY genes can ensue.The transcription factor DBP shows high-amplitude circadian oscillations 4,5 , and we found that Dbp transcription reaches its maximum and minimum at Zeitgeber time (ZT) 7 and ZT19, respectively (Fig. 1a), where ZT0 and ZT12 are the times when lights are switched on and off, respectively. Putative circadian regulatory regions containing E-box motifs have previously been mapped in the Dbp locus through the identification of DNase I-hypersensitive sites 6 , and genetic experiments have suggested that at least some of these might serve as binding sites for BMAL1 and CLOCK 6,7 . To examine whether these sites indeed bind CLOCK and BMAL1 in vivo, we have used a chromatin immunoprecipitation (ChIP) technique that we developed for the analysis of solid tissues (see Methods). For simplicity, the Dbp gene was subdivided into nine B800-bp segments according to the previously established map of DNase I hypersensitivity sites. ChIP experiments, performed with liver chromatin at 2-h intervals around the clock, suggested that both CLOCK and BMAL1 bind to ...

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Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome

Cited by 430 publications

References 23 publications

Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells

Differentially expressed genes are marked by histone 3 lysine 9 trimethylation in human cancer cells

MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer

Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions

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