Abstract
Genomic imprinting establishes parental allele-biased expression of a suite of mammalian genes based on parent-of-origin specific epigenetic marks. These marks are under the control of maternal effect proteins supplied in the oocyte. Here we report epigenetic repressor Smchd1 as a novel maternal effect gene that regulates the imprinted expression of ten genes in mice. We also found zygotic SMCHD1 had a dose-dependent effect on the imprinted expression of seven genes. Together, zygotic and maternal SMCHD1 regulate three classic imprinted clusters and eight other genes, including non-canonical imprinted genes. Interestingly, the loss of maternal SMCHD1 does not alter germline DNA methylation imprints pre-implantation or later in gestation. Instead, what appears to unite most imprinted genes sensitive to SMCHD1 is their reliance on polycomb-mediated methylation as germline or secondary imprints, therefore we propose that SMCHD1 acts downstream of polycomb imprints to mediate its function.
Highlights
Genomic imprinting describes the process that enables monoallelic expression of a set of genes according to their parent-of-origin (McGrath and Solter, 1984; Surani et al, 1984)
Contrary to previous reports where SMCHD1 depletion by siRNA knockdown in pre-implantation embryos resulted in reduced blastocyst formation, hatching and survival to term (Midic et al, 2018; Ruebel et al, 2019), we found no embryonic or preweaning lethality following the maternal deletion of Smchd1 (Figure 1—figure supplement 1a), and normal weights at P2 (Figure 1—figure supplement 1b)
We have discovered SMCHD1 is a novel maternal effect gene required for genomic imprinting
Summary
Genomic imprinting describes the process that enables monoallelic expression of a set of genes according to their parent-of-origin (McGrath and Solter, 1984; Surani et al, 1984). These imprinted genes are located in clusters. Imprinted expression is enabled by germline DNA methylation or histone methylation imprints that resist pre-implantation reprogramming and retain their parentof-origin specific marks (Ferguson-Smith, 2011; Barlow and Bartolomei, 2014; Inoue et al, 2017a; Inoue et al, 2018). The clusters controlled by germline DNA methylation imprints are classically described as the canonical imprinted genes. For the canonical imprinted genes, these can include both DNA methylation and histone methylation that occur post-fertilization dependent on the germline imprint (Hanna et al, 2019)
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