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

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.MYST | histone acetyltransferase | lysine acetyltransferase | BMI1 | polycomb

MOZ directs the distal-less homeobox gene expression program during craniofacial development

“…Moz mRNA is expressed widely in most or all cells at all stages of mouse embryonic development examined (E7.5, E8.5, E9.5, E10.5 and E13.5), including in the maxillary component of the first pharyngeal arch, which gives rise to the secondary palate (Sheikh et al, 2015a;Thomas et al, 2006;Voss et al, 2009). We have previously reported craniofacial defects in MOZ-deficient mouse foetuses, including micrognathia and a complete cleft of the secondary palate (Voss et al, 2012).…”

Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease

“…Therefore, the Sas3-Rfc1 and Enok-Elg1 interactions suggest an evolutionarily conserved link between the KAT6 complexes and the RFClike complexes. Second, MOZ has been shown to genetically interact with the polycomb protein BMI1 in regulating HOX gene activation (60). Together with the finding that Enok copurified with the repressive PRC1 complex (49), these observations suggest that the activator KAT6 complex may associate with PRC1 at specific gene loci to dynamically regulate gene expression during development.…”

“…MOZ can interact with AML1 and PU.1, two essential transcriptional factors for hematopoiesis, and enhance AML1-and PU.1-dependent transcription (57,58). Furthermore, several studies have shown that MOZ activates the expression of HOX genes in embryos and blood cells by acetylating H3K9 (30,42,59,60), suggesting another mechanism underlying the roles of MOZ in hematopoiesis, since HOX genes are critical for the development of the hematopoietic system (reviewed in reference 61). Similar to the importance of MOZ in hematopoietic stem cell renewal, both MOZ and BRPF1 are involved in the maintenance of neural stem cells (55,62), raising the possibility that the MOZ complex has a general role in maintaining stem cells.…”

Bivalent complexes of PRC1 with orthologs of BRD4 and MOZ/MORF target developmental genes in Drosophila

“…Our results are consistent with recent studies in which PRC1 is found on active genes in many systems (Schaaf et al 2013;Pemberton et al 2014;van den Boom et al 2016), and PRC1 targeting is largely independent of PRC2 (Kahn et al 2016). Most exciting is the likely conservation in zebrafish (Laue et al 2008) and mice (Sheikh et al 2015), based on the opposing genetic activities of PRC1 and MOZ/MORF complexes in regulation of the Hox genes. The reliance on a universal transducer of transcription factor activity in developmental decisions would be an elegant solution to the problem of widespread binding of sequence-specific regulators, as, in our model, only local interactions with preset bivalency will result in functional consequences.…”