Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is a non-canonical SMC protein that plays a key role in X chromosome inactivation and the epigenetic silencing of several clustered gene families, including the Hox clusters. Jansz et al., found that zygotic Smchd1-null mouse embryos displayed precocious activation of the Hox genes responsible for posterior vertebral patterning and consequential posterior-shift homeotic transformations in their skeletons.
Recently, we found that maternal SMCHD1 also plays a role in Hox gene silencing. Wanigasuriya, Gouil et al., showed that zygotic SMCHD1 is not present until the 16-32 cell stage of development, so the only SMCHD1 protein present in the zygote until that point is supplied by the oocyte. We have shown that E17.5 Smchd1 embryos which lack maternal Smchd1 (Smchd1 matΔ) have a posterior shift homeotic transformation of the seventh cervical vertebral element (C7) to a thoracic element (T1). RNA-sequencing of E8.5 tailbud tissue and an ESC-to-NMP differentiation series of Smchd1wildtype and matΔ embryos show a modest but consistent upregulation of anterior Hox genes.
To assess how maternal SMCHD1is able to regulate Hox gene expression post-implantation, carried our CUT&RUN for the Polycomb repressive complex marks H3K27me3 and H2AK119ub in our ESC model. We found no difference in the coverage density of these chromatin marks over the Hox clusters between Smchd1 wildtype and matΔ ESC lines, indicating that maternal Smchd1 acts downstream of Polycomb. Taken together our data suggests a model where maternal SMCHD1 sets up a chromatin state preimplantation that is required for appropriate Hox gene expression post-implantation, which we are now investigating.