9840.full.pdf (1.33 MB)
Download file

Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells

Download (1.33 MB)
journal contribution
posted on 10.06.2015, 12:03 by Shereen Jamaladdin, Richard D. W. Kelly, Laura O’Regan, Oliver M. Dovey, Grace E. Hodson, Christopher J. Millard, Nicola Portolano, Andrew M. Fry, John W. R. Schwabe, Shaun M. Cowley
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.

History

Citation

Proceedings of the National Academy of Sciences, 2014, 111 (27), pp 9840-9845

Version

VoR (Version of Record)

Published in

Proceedings of the National Academy of Sciences

Publisher

National Academy of Sciences

eissn

1091-6490

Copyright date

2014

Available date

10/06/2015

Publisher version

http://www.pnas.org/content/111/27/9840.abstract

Language

en

Usage metrics

Categories

Keywords

Exports