An H2A histone isotype regulates estrogen receptor target genes by mediating enhancer-promoter-3′-UTR interactions in breast cancer cells

Su, Chia-Hsin; Tzeng, Tsai-Yu; Cheng, Ching Wei; Hsu, Ming

doi:10.1093/nar/gkt1341

Cited by 14 publications

(29 citation statements)

References 45 publications

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“…Interestingly, the levels of H2A 1C and H2A 1B/E displayed a statistically significant increase as the cells became more tumorigenic. This observation is consistent with the recent report that increased levels of H2A 1C are seen in estrogen receptor positive breast cancers [ 16 ]. Changes in less abundant H2A species were also observed, such as the mono-methylated form of H2A 1H which decreased in abundance as the breast cancer cells became more malignant (Table 2 ).…”

Section: Resultssupporting

confidence: 94%

Proteomic profiling identifies specific histone species associated with leukemic and cancer cells

et al. 2015

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BackgroundChromatin is an extraordinarily complex structure. Much of this complexity results from the presence of numerous histone post-translational modifications and histone variants. Alterations in the patterns of histone post-translational modifications are emerging as a feature of many types of cancer and have been shown to have prognostic value.ResultsWe have applied a liquid chromatography/mass spectrometry-based approach to comprehensively characterize the histone proteome in primary samples from chronic lymphocytic leukemia (CLL) patients, as well as bladder and breast cancer cell culture models. When compared to non-malignant CD19+ B cells from healthy donors, the CLL histone proteome showed a distinct signature of differentially expressed species, spanning all the histones studied and including both post-translationally modified species and unmodified, non-allelic replication-dependent histone isoforms. However, the large changes in histone H3 and H4 that are characteristic of many cancer types were not observed. One of species of H2A (mass = 14,063 Da) was the most strongly associated with time to treatment in CLL patients. CLL patient samples also demonstrated histone profiles that were distinct from those of the bladder and breast cancer cells.ConclusionsSignatures of histone profiles are complex and can distinguish between healthy individuals and CLL patients and may provide prognostic markers. In addition, histone profiles may define tissue specific malignancies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12014-015-9095-4) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 94%

Proteomic profiling identifies specific histone species associated with leukemic and cancer cells

et al. 2015

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“…Differential expression of H2B1B had not been identified before, but low-H2B1M expression was identified as a biomarker for breast cancer and gastric cancer progression in microarray and proteomics studies [ 42 , 43 ]. Previous investigations of canonical H2A isoforms found that up-regulation of specific H2A sequences in chronic lymphocytic leukemia and in MCF-7 breast cancer cells caused increased proliferation and carcinogenesis in those cell types [ 44 , 45 ]. Similar studies should be performed by overexpressing H2B1B and H2B1M in some of the cancer cells where the levels of these variants are very low to see if this causes a decrease in cancer cell proliferation or progression.…”

Section: Discussionmentioning

confidence: 99%

Multi-faceted quantitative proteomics analysis of histone H2B isoforms and their modifications

Molden

Bhanu

LeRoy

et al. 2015

Epigenetics & Chromatin

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BackgroundHistone isoforms and their post-translational modifications (PTMs) play an important role in the control of many chromatin-related processes including transcription and DNA damage. Variants of histones H2A and H3 have been studied in depth and have been found to have distinct functions. Although 13 somatic histone H2B isoforms have been identified by various biochemical and mass spectrometric (MS) approaches, the distinct roles of these isoforms within human cells are as yet unknown. Here, we have developed quantitative MS techniques to characterize isoform-specific H2B expression across the cell cycle, in differentiated myogenic cells, and in different cancer cell lines to illuminate potential functional roles.ResultsUsing the MS strategies that we developed, we identified differences in H2B isoform levels between different cancer cell types, suggesting cancer or tissue-specific H2B isoform regulation. In particular, we found large variations in the levels of isoforms H2B1B and H2B1M across the panel of cell lines. We also found that, while individual H2B isoforms do not differ in their acetylation levels, trends in the acetylation on all H2B isoforms correlated with acetylation on other histone family members in the cancer cell line panel. We also used the MS strategies to study H2B protein expression across the cell cycle and determined that H2B isoforms that are alternatively spliced to carry a polyadenylation signal rather than the standard histone downstream element are expressed independently of the cell cycle. However, the level of protein produced from the polyadenylated transcripts does not contribute significantly to the total pool of H2B isoforms translated across the cell cycle or in non-cycling myogenic cells.ConclusionsOur results show that H2B isoforms are expressed at varying levels in different cells, suggesting isoform-specific, and possibly cell-type-specific, H2B gene regulation. The bottom-up mass spectrometry technique we developed for H2B quantification is compatible with the current standard histone H3 and H4 bottom-up ‘one-pot’ analysis platform so that H2B isoforms and their modifications can be studied in future experiments at the same time as histone H3 and H4 modifications. Therefore, we have expanded the histone landscape that can be interrogated in future experiments.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0006-8) contains supplementary material, which is available to authorized users.

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“…Furthermore, over-expression of a truncated ERα, lacking the DNA-binding domain (ERα 264–595 ) [24], decreased the induction of IL-20 expression in E2-induced MCF-7 cells (Fig 2B). As expected, both over-expression of ERα 264–595 and treatment with ICI inhibited the recruitment of RNA Pol II to IL-20 chromatin (Fig 2E).…”

Section: Resultsmentioning

confidence: 99%

“…The dynamic assembly and dissolution of co-regulators from estrogen responsive promoters following E2-liganded ERα activation and deactivation turns the basal transcription machinery ‘on’ and ‘off’, respectively [37,38]. Within 30 min of the addition of estrogen, co-regulators such as SRC-1, AIB1, H2A.Z, H2ac, and p300 are rapidly recruited to ERα binding sites to activate the expression of ERα target genes [24,37,38]. Furthermore, ERα can recruit histone demethylase enzymes KDM3A, KDM4B, and KDM6B to ERα targeted chromatin to assert histone modification changes [39–41].…”

Section: Discussionmentioning

confidence: 99%

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Regulation of IL-20 Expression by Estradiol through KMT2B-Mediated Epigenetic Modification

Su¹,

Lin²,

Tzeng³

et al. 2016

PLoS ONE

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Cytokines are low molecular weight regulatory proteins, or glycoproteins, with both tumor-promoting and inhibitory effects on breast cancer growth. Different cytokines play important roles in breast cancer initiation and progression. Here, we show that of the 39 interleukin (IL) genes, IL-20 is the only gene over-expressed in MCF-7 cells treated with estradiol (E2) and that induction of IL-20 expression by estrogen was epigenetically regulated. Methylation of histone H3K4 in the IL-20 promoter was shown to occur via the specific recruitment of KMT2B by estrogen receptor alpha (ERα), but not by other members of the mixed-lineage leukemia (MLL) family of histone methyltransferases. Depletion of KMT2B, or IL-20, disrupts estrogen signaling, attenuates cell proliferation, reduces colony formation, and results in cell cycle arrest. Furthermore, we demonstrated that KMT2B-mediated epigenetic modification also affected the expression of several ERα target genes. IL-20 and KMT2B expression were also associated with ERα-positive breast cancer tissues. We have revealed an important role for KMT2B in the epigenetic transcriptional regulation of cytokine IL-20, and other ERα-responsive genes, in breast cancer cells. Inhibition of IL-20 and KMT2B may have therapeutic benefits in ERα-positive breast cancer.

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An H2A histone isotype regulates estrogen receptor target genes by mediating enhancer-promoter-3′-UTR interactions in breast cancer cells

Cited by 14 publications

References 45 publications

Proteomic profiling identifies specific histone species associated with leukemic and cancer cells

Proteomic profiling identifies specific histone species associated with leukemic and cancer cells

Multi-faceted quantitative proteomics analysis of histone H2B isoforms and their modifications

Regulation of IL-20 Expression by Estradiol through KMT2B-Mediated Epigenetic Modification

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