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Title: Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells
Authors: Jamaladdin, Shereen
Kelly, Richard D. W.
O’Regan, Laura
Dovey, Oliver M.
Hodson, Grace E.
Millard, Christopher J.
Portolano, Nicola
Fry, Andrew M.
Schwabe, John W. R.
Cowley, Shaun M.
First Published: 23-Jun-2014
Publisher: National Academy of Sciences
Citation: Proceedings of the National Academy of Sciences, 2014, 111 (27), pp 9840-9845
Abstract: Histone deacetylases 1 and 2 (HDAC1/2) form the core catalytic components of corepressor complexes that modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an ES cell line in which Hdac1 and Hdac2 can be inactivated simultaneously. Loss of HDAC1/2 resulted in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is dependent upon cell cycle progression, because differentiated, nonproliferating cells retain their viability. Furthermore, we observe increased mitotic defects, chromatin bridges, and micronuclei, suggesting HDAC1/2 are necessary for accurate chromosome segregation. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2-deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog, Esrrb, and Rex1. HDAC1/2 activity is regulated through binding of an inositol tetraphosphate molecule (IP4) sandwiched between the HDAC and its cognate corepressor. This raises the important question of whether IP4 regulates the activity of the complex in cells. By rescuing the viability of double-knockout cells, we demonstrate for the first time (to our knowledge) that mutations that abolish IP4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have essential and pleiotropic roles in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors.
DOI Link: 10.1073/pnas.1321330111
eISSN: 1091-6490
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2014, National Academy of Sciences. Freely available online through the PNAS open access option.
Appears in Collections:Published Articles, Dept. of Biochemistry

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