MOZ and BMI1 play opposing roles during Hox gene activation in ES cells and in body segment identity specification in vivo

Sheikh, BN; Downer, NL; Phipson, B; Vanyai, HK; Kueh, AJ; McCarthy, DJ; Smyth, GK; Thomas, T; Voss, AK

Author(s): Sheikh, BN; Downer, NL; Phipson, B; Vanyai, HK; Kueh, AJ; McCarthy, DJ; Smyth, GK; Thomas, T; Voss, AK;
Details: Publication Year 2015-04-28,Volume 112,Issue #17,Page 5437-42
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Publication Type: Journal Article
Abstract: Hox genes underlie the specification of body segment identity in the anterior-posterior axis. They are activated during gastrulation and undergo a dynamic shift from a transcriptionally repressed to an active chromatin state in a sequence that reflects their chromosomal location. Nevertheless, the precise role of chromatin modifying complexes during the initial activation phase remains unclear. In the current study, we examined the role of chromatin regulators during Hox gene activation. Using embryonic stem cell lines lacking the transcriptional activator MOZ and the polycomb-family repressor BMI1, we showed that MOZ and BMI1, respectively, promoted and repressed Hox genes during the shift from the transcriptionally repressed to the active state. Strikingly however, MOZ but not BMI1 was required to regulate Hox mRNA levels after the initial activation phase. To determine the interaction of MOZ and BMI1 in vivo, we interrogated their role in regulating Hox genes and body segment identity using Moz;Bmi1 double deficient mice. We found that the homeotic transformations and shifts in Hox gene expression boundaries observed in single Moz and Bmi1 mutant mice were rescued to a wild type identity in Moz;Bmi1 double knockout animals. Together, our findings establish that MOZ and BMI1 play opposing roles during the onset of Hox gene expression in the ES cell model and during body segment identity specification in vivo. We propose that chromatin-modifying complexes have a previously unappreciated role during the initiation phase of Hox gene expression, which is critical for the correct specification of body segment identity.
Publisher: National Academy of Sciences
Research Division(s): Development And Cancer; Bioinformatics
PubMed ID: 25922517
Publisher's Version: https://doi.org/10.1073/pnas.1422872112
Open Access at Publisher's Site: http://www.pnas.org/content/112/17/5437.long
NHMRC Grants: NHMRC/1010851, NHMRC/1008699, NHMRC/1030704, NHMRC/1051078, NHMRC/1058892, NHMRC/1003435, NHMRC/575512, NHMRC/1081421,
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Creation Date: 2015-05-20 09:04:11

Last Modified: 2015-05-20 09:46:56