Histone crosstalk directed by H2B ubiquitination is required for chromatin boundary integrity

Ma, M.K.-W. , Heath, C. , Hair, A. and West, A. (2011) Histone crosstalk directed by H2B ubiquitination is required for chromatin boundary integrity. PLoS Genetics, 7(7), e1002175. (doi: 10.1371/journal.pgen.1002175) (PMID:21811414) (PMCID:PMC3140996)

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Abstract

Genomic maps of chromatin modifications have provided evidence for the partitioning of genomes into domains of distinct chromatin states, which assist coordinated gene regulation. The maintenance of chromatin domain integrity can require the setting of boundaries. The HS4 insulator element marks the 3′ boundary of a heterochromatin region located upstream of the chicken β-globin gene cluster. Here we show that HS4 recruits the E3 ligase RNF20/BRE1A to mediate H2B mono-ubiquitination (H2Bub1) at this insulator. Knockdown experiments show that RNF20 is required for H2Bub1 and processive H3K4 methylation. Depletion of RNF20 results in a collapse of the active histone modification signature at the HS4 chromatin boundary, where H2Bub1, H3K4 methylation, and hyperacetylation of H3, H4, and H2A.Z are rapidly lost. A remarkably similar set of events occurs at the HSA/HSB regulatory elements of the FOLR1 gene, which mark the 5′ boundary of the same heterochromatin region. We find that persistent H2Bub1 at the HSA/HSB and HS4 elements is required for chromatin boundary integrity. The loss of boundary function leads to the sequential spreading of H3K9me2, H3K9me3, and H4K20me3 over the entire 50 kb FOLR1 and β-globin region and silencing of FOLR1 expression. These findings show that the HSA/HSB and HS4 boundary elements direct a cascade of active histone modifications that defend the FOLR1 and β-globin gene loci from the pervasive encroachment of an adjacent heterochromatin domain. We propose that many gene loci employ H2Bub1-dependent boundaries to prevent heterochromatin spreading.

Item Type:Articles
Additional Information:This is an open-access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/3.0/">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:West, Dr Adam and Heath, Dr Carol and Hair, Dr Alan
Authors: Ma, M.K.-W., Heath, C., Hair, A., and West, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN:1553-7390
ISSN (Online):1553-7404
Copyright Holders:Copyright © 2011 Ma et al.
First Published:First published in PLoS Genetics 7 (7) : e1002175
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
365431Histone modifications at chromatin boundary elementsAdam WestBiotechnology and Biological Sciences Research Council (BBSRC)BBS/B/08043Institute of Cancer Sciences
381911Understanding chromatin insulator elements and their roles in gene transcriptionAdam WestMedical Research Council (MRC)G0400180Institute of Cancer Sciences