Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo

Abstract

Parents transmit genetic and epigenetic information to their offspring. Maternal effect genes regulate the offspring epigenome to ensure normal development. Here we report that the epigenetic regulator SMCHD1 has a maternal effect on Hox gene expression and skeletal patterning. Maternal SMCHD1, present in the oocyte and preimplantation embryo, prevents precocious activation of Hox genes post-implantation. Without maternal SMCHD1, highly penetrant posterior homeotic transformations occur in the embryo. Hox genes are decorated with Polycomb marks H2AK119ub and H3K27me3 from the oocyte throughout early embryonic development; however, loss of maternal SMCHD1 does not alter these marks. Therefore, we propose maternal SMCHD1 acts downstream of Polycomb marks to establish a chromatin state necessary for persistent epigenetic silencing and appropriate Hox gene expression later in the developing embryo. This is a striking role for maternal SMCHD1 in long-lived epigenetic effects impacting offspring phenotype.

Maternal SMCHD1 controls both imprinted Xist expression and imprinted X chromosome inactivation

“…In addition, failed gene silencing was associated with a failure to methylate CpG islands on the Xi to the same level as the wild-type. This persisting disruption to epigenetic silencing bore similarities two other maternal effects seen in embryos with maternal Smchd1 deletions: the partial loss of autosomal imprinting in the mid-gestation placentae (Wanigasuriya et al, 2020) and the disrupted Hox gene regulation in tissue of the embryo-proper (Benetti et al, 2021).…”

“…What this particular epigenetic state is and how SMCHD1 creates it remains obscure, but it is tempting to speculate that, like for SMCHD1 recruitment, a single mechanism explains SMCHD1’s mode of action for both maternal and zygotic SMCHD1, at all of its diverse targets. SMCHD1 is required for the repression of Hox genes, protocadherin clusters, imprinted genes, the inactive X, and tandem repeat arrays ( Jansz et al, 2018a ; Benetti et al, 2021 ; Gendrel et al, 2012 ; Chen et al, 2015 ; Mould et al, 2013 ; Blewitt et al, 2008 ; Lemmers et al, 2012 ; Gdula et al, 2019 ). All these targets display abundant Polycomb marks.…”

HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring

“…We were unable to ascertain whether these observed axial transformations were due to a maternal or zygotic loss of gene activity as all Smchd1 knockout females were embryonic lethal. However, this conundrum has been recently addressed by Benetti and colleagues 22 who have shown, using an oocyte-specific Cremediated deletion of maternal of Smchd1, that the maternal pool of Smchd1 has an important role in repressing Hox expression and that also leads to vertebral patterning defects in pups born to mothers lacking Smchd1 only during oogenesis. These results are consistent with those made in zebrafish and confirm that Smchd1 is essential in the maternal germline, before fertilization, to control the expression of Hox genes in future embryos.…”