期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：17
页码：5437-5442
DOI：10.1073/pnas.1422872112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe body is patterned in the anterior-posterior axis by the correct spatial and temporal expression of Hox genes during embryonic development. One mechanism critical for the precise spatiotemporal expression of Hox genes is the chromatin state. While changes in chromatin conformation during the activation of Hox genes have been well described, the importance of the factors that in turn regulate chromatin remains enigmatic and controversial. In the current study, we investigate the role of two critical chromatin regulators, MOZ and BMI1, during Hox gene activation and in specifying body segment identity. We establish the importance of MOZ and BMI1 during the initial activation of Hox genes in ES cells and in correctly specifying body segment identity during embryonic development. 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.
