Histone H1x is highly expressed in human neuroendocrine cells and tumours

Warneboldt, Julia; Haller, Florian; Horstmann, O.; Danner, Bernhard C.; Füzesi, L.; Doenecke, Detlef; Happel, Nicole

doi:10.1186/1471-2407-8-388

Cited by 26 publications

(17 citation statements)

References 27 publications

(25 reference statements)

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“…Deletion of three major somatic H1 variants (H1c, H1d and H1e) together leads to a 50% reduction of the total H1 level and embryonic lethality at midgestation, demonstrating that H1 level is critical for mammalian development [7]. H1 variants are conserved from mouse to human, and differ in their biochemical properties and expression patterns during development and malignant transformation [8]–[11]. Although none of the H1 variants tested is essential for mouse development [12]–[15], they have been shown to regulate specific gene expression in various cell types [6], [16]–[18].…”

Section: Introductionmentioning

confidence: 99%

High-Resolution Mapping of H1 Linker Histone Variants in Embryonic Stem Cells

et al. 2013

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H1 linker histones facilitate higher-order chromatin folding and are essential for mammalian development. To achieve high-resolution mapping of H1 variants H1d and H1c in embryonic stem cells (ESCs), we have established a knock-in system and shown that the N-terminally tagged H1 proteins are functionally interchangeable to their endogenous counterparts in vivo. H1d and H1c are depleted from GC- and gene-rich regions and active promoters, inversely correlated with H3K4me3, but positively correlated with H3K9me3 and associated with characteristic sequence features. Surprisingly, both H1d and H1c are significantly enriched at major satellites, which display increased nucleosome spacing compared with bulk chromatin. While also depleted at active promoters and enriched at major satellites, overexpressed H10 displays differential binding patterns in specific repetitive sequences compared with H1d and H1c. Depletion of H1c, H1d, and H1e causes pericentric chromocenter clustering and de-repression of major satellites. These results integrate the localization of an understudied type of chromatin proteins, namely the H1 variants, into the epigenome map of mouse ESCs, and we identify significant changes at pericentric heterochromatin upon depletion of this epigenetic mark.

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Section: Introductionmentioning

confidence: 99%

High-Resolution Mapping of H1 Linker Histone Variants in Embryonic Stem Cells

et al. 2013

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“…Histone H1x is a member of the H1 histone family that stabilizes chromatin in a compact structure; it also acts as a structural protein, regulating gene expression, participating in chromatin-based processes such as DNA replication and repair, and therefore having a potential role in malignant transformation. 50 Warneboldt et al 50 investigated the expression of H1x in thirteen primary NETs and a liver metastasis, and demonstrated an increased expression of H1x in NET tissues compared with normal tissues. Magerl et al 51 studied demethylation of histone H3 at lysine 4 (H3K4diMe) in sixteen low-grade GI-NETs and reported a strong expression of H3Kdi4diME in 93% of samples, suggesting a potential role of histone H3K4 modification in intestinal NETs.…”

Section: Pancreatic Neuroendocrine Tumoursmentioning

confidence: 98%

“…DNMT inhibitors DNMT inhibitors (DNMTIs) have shown clinical efficacy in the management of haematological malignancies, but have not been extensively investigated in NETs. 50 Habbe et al 63 carried out one of the first studies evaluating the potential therapeutic role of the demethylating agent, decitabine, in vitro. They reported differential expression of forty-eight genes following decitabine treatment including high expression of 25/48 (52%) genes.…”

Section: Epigenetic Profile Of Net and Drug Treatmentmentioning

confidence: 99%

Epigenetic changes in gastroenteropancreatic neuroendocrine tumours

et al. 2014

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An understanding of epigenetic drivers of tumorigenesis has developed rapidly during the last years. The identification of these changes including DNA methylation and histone modifications in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is a step forward in trying to define underlying biologic processes in this heterogeneous disease. The reversible nature of these changes represents a potential therapeutic target. We present an overview of the current knowledge of epigenetic alterations related to GEP-NETs, focusing on the influence and impact these changes have on pathogenesis and prognosis. The potential role of demethylating agents in the management of this patient population is discussed.

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“…Histone H1x has been demonstrated to be highly expressed in NETs but also in the corresponding nonneoplastic neuroendocrine cells of the pancreas and small intestine and therefore may reflect cell of origin rather than tumorigenic feature (Warneboldt et al 2008).…”

Section: Histone Modifications In Gastrointestinal Netmentioning

confidence: 99%

Neuroendocrine tumours: cracking the epigenetic code

Karpathakis¹,

Dibra²,

Thirlwell³

2013

Endocrine-Related Cancer

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The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. Determination of epigenetic modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as DNA methylation at RASSF1A are frequent findings in NETs of all origins and may be associated with worse prognosis. MicroRNA signatures and histone modifications have been identified which can differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic uncertainty. Historically, candidate genedriven approaches have yielded limited insight into the epigenetics of NET. Recent progress has been facilitated by development of high-throughput tools including second-generation sequencing and arrays for analysis of the 'epigenome' of tumour and normal tissue, permitting unbiased approaches such as exome sequencing that identified mutations of chromatin-remodelling genes ATRX/DAXX in 44% of pancreatic NETs. Epigenetic changes are reversible and therefore represent an attractive therapeutic target; to date, clinical outcomes of epigenetic therapies in solid tumours have been disappointing; however, in vitro studies on NETs are promising and further clinical trials are required to determine utility of this class of novel agents. In this review, we perform a comprehensive evaluation of epigenetic changes found in NETs to date, including rare NETs such as phaeochromocytoma and adrenocortical tumours. We suggest priorities for future research and discuss potential clinical applications and novel therapies.

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Histone H1x is highly expressed in human neuroendocrine cells and tumours

Cited by 26 publications

References 27 publications

High-Resolution Mapping of H1 Linker Histone Variants in Embryonic Stem Cells

High-Resolution Mapping of H1 Linker Histone Variants in Embryonic Stem Cells

Epigenetic changes in gastroenteropancreatic neuroendocrine tumours

Neuroendocrine tumours: cracking the epigenetic code

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