Mapping of six somatic linker histone H1 variants in human breast cancer cells uncovers specific features of H1.2

Millán-Ariño, Lluís; Islam, Abul B.M.M.K.; Izquierdo‐Bouldstridge, Andrea; Mayor, Regina; Terme, Jean-Michel; Luque, Neus; Sancho, Mónica; López‐Bigas, Núria; Jordan, Albert

doi:10.1093/nar/gku079

Cited by 97 publications

(147 citation statements)

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“…Expression of H1.4-K26A induced both up-and down-regulation of gene expression compared with H1.4-WT expression, consistent with both active and repressive effects of H1.4-K26 PTMs. Very few genes presented altered expression in opposite senses whether H1.4 was overexpressed or knocked down, and we do not believe that this is due to specific binding of H1.4 to these promoters, as we have previously reported that all gene promoters are bound by any H1 variant quite indistinctly [42]. We have shown here that a subset of genes differentially expressed upon H1.4 overexpression do not contain significant enrichment of this variant.…”

Section: Discussionsupporting

confidence: 44%

“…4). Active genes (CDK2, JUN), but not repressed genes (NANOG), showed local H1.2 (WT or mutant) depletion at the transcription start sites (TSS) compared with the corresponding upstream promoter region, as described elsewhere [33,42].…”

Section: Resultsmentioning

confidence: 78%

“…To test if the genes found to be differentially expressed upon H1.4 expression that depended on K26 are normally enriched/ depleted for H1.4 we took our ChIP-seq data on H1.4-HA distribution [42] and look at the number of enriched and depleted islands on those genes compared to random samples of the same number of genes (see Supplementary data, S12). Although up-regulated genes presented more H1.4 (and other H1 variants, data not shown) enrichment islands and less depletion islands than random genes, P-values indicated that this was not significant.…”

Section: Resultsmentioning

confidence: 99%

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Dynamics and dispensability of variant‐specific histone H1 Lys‐26/Ser‐27 and Thr‐165 post‐translational modifications

et al. 2014

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a b s t r a c tIn mammals, the linker histone H1, involved in DNA packaging into chromatin, is represented by a family of variants. H1 tails undergo post-translational modifications (PTMs) that can be detected by mass spectrometry. We developed antibodies to analyze several of these as yet unexplored PTMs including the combination of H1.4 K26 acetylation or trimethylation and S27 phosphorylation. H1.2-T165 phosphorylation was detected at S and G2/M phases of the cell cycle and was dispensable for chromatin binding and cell proliferation; while the H1.4-K26 residue was essential for proper cell cycle progression. We conclude that histone H1 PTMs are dynamic over the cell cycle and that the recognition of modified lysines may be affected by phosphorylation of adjacent residues.

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Section: Discussionsupporting

confidence: 44%

Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

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Dynamics and dispensability of variant‐specific histone H1 Lys‐26/Ser‐27 and Thr‐165 post‐translational modifications

et al. 2014

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“…Knock-out of Hmgn1 and Hmgn2 in mouse embryo fibroblasts results in the loss of DNase I-hypersensitive sites, particularly at enhancer regions (63). In breast cancer cells, the depletion of certain H1 subtypes, including H1.2, is associated with histone marks indicative of strong enhancers (37). A recent publication has also shown that the pioneer factor forkhead box A (FOXA) displaces H1 at enhancers in mouse hepatocytes, and the displacement of H1 promotes accessibility of the underlying nucleosomes and binding of liver-specific transcription factors (64).…”

Section: Discussionmentioning

confidence: 99%

Histone H1 and Chromosomal Protein HMGN2 Regulate Prolactin-induced STAT5 Transcription Factor Recruitment and Function in Breast Cancer Cells

Schauwecker

Kim

Licht

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuThe hormone prolactin (PRL) contributes to breast cancer pathogenesis through various signaling pathways, one of the most notable being the JAK2/signal transducer and activator of transcription 5 (STAT5) pathway. PRL-induced activation of the transcription factor STAT5 results in the up-regulation of numerous genes implicated in breast cancer pathogenesis. However, the molecular mechanisms that enable STAT5 to access the promoters of these genes are not well understood. Here, we show that PRL signaling induces chromatin decompaction at promoter DNA, corresponding with STAT5 binding. The chromatin-modifying protein high mobility group nucleosomal binding domain 2 (HMGN2) specifically promotes STAT5 accessibility at promoter DNA by facilitating the dissociation of the linker histone H1 in response to PRL. Knockdown of H1 rescues the decrease in PRL-induced transcription following HMGN2 knockdown, and it does so by allowing increased STAT5 recruitment. Moreover, H1 and STAT5 are shown to function antagonistically in regulating PRL-induced transcription as well as breast cancer cell biology. While reduced STAT5 activation results in decreased PRL-induced transcription and cell proliferation, knockdown of H1 rescues both of these effects. Taken together, we elucidate a novel mechanism whereby the linker histone H1 prevents STAT5 binding at promoter DNA, and the PRL-induced dissociation of H1 mediated by HMGN2 is necessary to allow full STAT5 recruitment and promote the biological effects of PRL signaling.In the mammary gland, signals from the polypeptide hormone prolactin (PRL) are essential for normal development (1-4), and these physiological effects are mediated through the homologous transcription factors signal transducer and activator of transcription 5a and 5b (referred to as STAT5) (5). PRL signals by binding to the PRL receptor (PRLR), 2 a transmembrane receptor of the cytokine receptor superfamily. Binding of PRL to the PRLR results in the activation of STAT5 via phosphorylation by the tyrosine kinase Janus kinase 2 (JAK2) (6 -8). Phosphorylated STAT5 dimerizes, and the active STAT5 dimers translocate to the nucleus. In the nucleus, STAT5 recognizes and binds to consensus elements in the DNA, which induces the expression of STAT5 target genes (9).PRL-induced STAT5 activation results in the up-regulation of many pro-proliferative genes (10 -12). Although essential for proper mammary gland development, aberrant PRL signaling and STAT5 activation also contribute to breast cancer pathogenesis. Transgenic mice that overexpress PRL in the mammary epithelium develop mammary tumors, which can be either estrogen receptor-positive or -negative (13). In epidemiologic studies, women with elevated serum PRL are at an increased risk of developing breast cancer (14 -17). PRL also enhances the proliferation, motility, and survival of breast cancer cells (18 -20). Similarly, overexpression of STAT5 in the mammary gland of transgenic mice results in mammary tumor development (21), whereas hemizygous los...

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“…8E) or total H1 or H3 (data not shown) were observed. Moreover, these ChIP results confirmed that H1X was not the only H1 variant occupying these H1X-responsive promoters.We and others have reported elsewhere that there is a valley in H1 occupancy at active promoters compared with that in surrounding regions (40,41). We compared H1 occupancy at TSS and Ϫ3 kb upstream (the distal promoter).…”

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confidence: 99%

Genome Distribution of Replication-independent Histone H1 Variants Shows H1.0 Associated with Nucleolar Domains and H1X Associated with RNA Polymerase II-enriched Regions

Mayor¹,

Izquierdo‐Bouldstridge²,

Millán-Ariño³

et al. 2015

Journal of Biological Chemistry

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Background: There are seven histone H1 variants in somatic mammalian cells, two of which are replication-independent, H1.0 and H1X. Results: In breast cancer cells, H1.0 is enriched at nucleolus-associated domains, whereas H1X is associated with RNA polymerase II-enriched regions. Conclusion: Most H1 variants show great redundancy across the genome, but there is also some specificity. Significance: Some H1 variants may have specific functions.Unlike core histones, the linker histone H1 family is more evolutionarily diverse, and many organisms have multiple H1 variants or subtypes. In mammals, the H1 family includes seven somatic H1 variants; H1.1 to H1.5 are expressed in a replicationdependent manner, whereas H1.0 and H1X are replication-independent. Using ChIP-sequencing data and cell fractionation, we have compared the genomic distribution of H1.0 and H1X in human breast cancer cells, in which we previously observed differential distribution of H1.2 compared with the other subtypes. We have found H1.0 to be enriched at nucleolus-associated DNA repeats and chromatin domains, whereas H1X is associated with coding regions, RNA polymerase II-enriched regions, and hypomethylated CpG islands. Further, H1X accumulates within constitutive or included exons and retained introns and toward the 3 end of expressed genes. Inducible H1X knockdown does not affect cell proliferation but dysregulates a subset of genes related to cell movement and transport. In H1X-depleted cells, the promoters of up-regulated genes are not occupied specifically by this variant, have a lower than average H1 content, and, unexpectedly, do not form an H1 valley upon induction. We conclude that H1 variants are not distributed evenly across the genome and may participate with some specificity in chromatin domain organization or gene regulation.There are five major classes of histones that participate in the correct folding of eukaryotic DNA into chromatin: the core histones H2A, H2B, H3, and H4, which form an octamer and constitute the nucleosome core particle, and the linker histone H1, which binds to the nucleosomes near the entry/exit sites of linker DNA. Stabilization of the condensed states of chromatin is the function most commonly attributed to the linker histone (1, 2), in addition to its inhibitory effect in vitro on nucleosome mobility (3) and transcription (4).Histone H1 in humans is a family of closely related, single gene-encoded proteins, including seven somatic subtypes (H1.1 to H1.5, H1.0, and H1X), three testis-specific variants (H1t, H1T2, and HILS1), and one restricted to oocytes (H1oo) (5, 6). Among the somatic histone H1 variants, H1.1 to H1.5 are expressed in a replication-dependent manner, whereas H1.0 and H1X are replication-independent. The H1.1 to H1.5-encoding genes are clustered in a region of chromosome 6 together with the core histone genes, whereas the H1X and H1.0 genes are on chromosomes 3 and 22, respectively. H1.2 to H1.5 and H1X are ubiquitously expressed, H1.1 is restricted to certain tissues, and H1.0 accumulat...

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Mapping of six somatic linker histone H1 variants in human breast cancer cells uncovers specific features of H1.2

Cited by 97 publications

References 107 publications

Dynamics and dispensability of variant‐specific histone H1 Lys‐26/Ser‐27 and Thr‐165 post‐translational modifications

Dynamics and dispensability of variant‐specific histone H1 Lys‐26/Ser‐27 and Thr‐165 post‐translational modifications

Histone H1 and Chromosomal Protein HMGN2 Regulate Prolactin-induced STAT5 Transcription Factor Recruitment and Function in Breast Cancer Cells

Genome Distribution of Replication-independent Histone H1 Variants Shows H1.0 Associated with Nucleolar Domains and H1X Associated with RNA Polymerase II-enriched Regions

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