Maintenance of active chromatin states by HMGN2 is required for stem cell identity in a pluripotent stem cell model

Garza-Manero, S. et al. (2019) Maintenance of active chromatin states by HMGN2 is required for stem cell identity in a pluripotent stem cell model. Epigenetics and Chromatin, 12, 73. (doi: 10.1186/s13072-019-0320-7) (PMID:31831052) (PMCID:PMC6907237)

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Abstract

Background: Members of the HMGN protein family modulate chromatin structure and influence epigenetic modifications. HMGN1 and HMGN2 are highly expressed during early development and in the neural stem/progenitor cells of the developing and adult brain. Here, we investigate whether HMGN proteins contribute to the chromatin plasticity and epigenetic regulation that is essential for maintaining pluripotency in stem cells. Results: We show that loss of Hmgn1 or Hmgn2 in pluripotent embryonal carcinoma cells leads to increased levels of spontaneous neuronal differentiation. This is accompanied by the loss of pluripotency markers Nanog and Ssea1, and increased expression of the pro-neural transcription factors Neurog1 and Ascl1. Neural stem cells derived from these Hmgn-knockout lines also show increased spontaneous neuronal differentiation and Neurog1 expression. The loss of HMGN2 leads to a global reduction in H3K9 acetylation, and disrupts the profile of H3K4me3, H3K9ac, H3K27ac and H3K122ac at the Nanog and Oct4 loci. At endodermal/mesodermal genes, Hmgn2-knockout cells show a switch from a bivalent to a repressive chromatin configuration. However, at neuronal lineage genes whose expression is increased, no epigenetic changes are observed and their bivalent states are retained following the loss of HMGN2. Conclusions: We conclude that HMGN1 and HMGN2 maintain the identity of pluripotent embryonal carcinoma cells by optimising the pluripotency transcription factor network and protecting the cells from precocious differentiation. Our evidence suggests that HMGN2 regulates active and bivalent genes by promoting an epigenetic landscape of active histone modifications at promoters and enhancers.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:West, Dr Adam and West, Dr Katherine and Gurden, Ross and Jeantet, Valentine and Garza Manero, Sylvia and SINDI, Abdulmajeed
Authors: Garza-Manero, S., Sindi, A. A. A., Mohan, G., Rehbini, O., Jeantet, V. H.M., Bailo, M., Abdul Latif, F., West, M. P., Gurden, R., Finlayson, L., Svambaryte, S., West, A. G., and West, K. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Research Group:Katherine West
Journal Name:Epigenetics and Chromatin
Publisher:BioMed Central
ISSN:1756-8935
ISSN (Online):1756-8935
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Epigenetics and Chromatin 12: 73
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
581981The role of H2B ubiquitination in genome organisation.Adam WestBiotechnology and Biological Sciences Research Council (BBSRC)BB/J008605/1ICS - EPIGENETICS
632343MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16George BaillieMedical Research Council (MRC)MR/K501335/1MVLS GRADUATE SCHOOL