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Fam60a defines a variant Sin3a‐Hdac complex in embryonic stem cells required for self‐renewal 下载免费PDF全文
Gundula Streubel Darren J Fitzpatrick Giorgio Oliviero Andrea Scelfo Bruce Moran Sudipto Das Nayla Munawar Ariane Watson Kieran Wynne Gian Luca Negri Eugene T Dillon SriGanesh Jammula Karsten Hokamp Darran P O'Connor Diego Pasini Adrian P Bracken 《The EMBO journal》2017,36(15):2216-2232
Sin3a is the central scaffold protein of the prototypical Hdac1/2 chromatin repressor complex, crucially required during early embryonic development for the growth of pluripotent cells of the inner cell mass. Here, we compare the composition of the Sin3a‐Hdac complex between pluripotent embryonic stem (ES) and differentiated cells by establishing a method that couples two independent endogenous immunoprecipitations with quantitative mass spectrometry. We define the precise composition of the Sin3a complex in multiple cell types and identify the Fam60a subunit as a key defining feature of a variant Sin3a complex present in ES cells, which also contains Ogt and Tet1. Fam60a binds on H3K4me3‐positive promoters in ES cells, together with Ogt, Tet1 and Sin3a, and is essential to maintain the complex on chromatin. Finally, we show that depletion of Fam60a phenocopies the loss of Sin3a, leading to reduced proliferation, an extended G1‐phase and the deregulation of lineage genes. Taken together, Fam60a is an essential core subunit of a variant Sin3a complex in ES cells that is required to promote rapid proliferation and prevent unscheduled differentiation. 相似文献
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Mircea Winter Mirjam A Moser Dominique Meunier Katharina Mattes Christina Murko Christina Humer Tina Meischel Gerald Brosch Patrick Matthias Maria Sibilia Christian Seiser 《The EMBO journal》2013,32(24):3176-3191
The histone deacetylases HDAC1 and HDAC2 remove acetyl moieties from lysine residues of histones and other proteins and are important regulators of gene expression. By deleting different combinations of Hdac1 and Hdac2 alleles in the epidermis, we reveal a dosage‐dependent effect of HDAC1/HDAC2 activity on epidermal proliferation and differentiation. Conditional ablation of either HDAC1 or HDAC2 in the epidermis leads to no obvious phenotype due to compensation by the upregulated paralogue. Strikingly, deletion of a single Hdac2 allele in HDAC1 knockout mice results in severe epidermal defects, including alopecia, hyperkeratosis, hyperproliferation and spontaneous tumour formation. These mice display impaired Sin3A co‐repressor complex function, increased levels of c‐Myc protein, p53 expression and apoptosis in hair follicles (HFs) and misregulation of HF bulge stem cells. Surprisingly, ablation of HDAC1 but not HDAC2 in a skin tumour model leads to accelerated tumour development. Our data reveal a crucial function of HDAC1/HDAC2 in the control of lineage specificity and a novel role of HDAC1 as a tumour suppressor in the epidermis. 相似文献
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TIS7 regulation of the beta-catenin/Tcf-4 target gene osteopontin (OPN) is histone deacetylase-dependent 总被引:2,自引:0,他引:2
Vietor I Kurzbauer R Brosch G Huber LA 《The Journal of biological chemistry》2005,280(48):39795-39801