SMCHD1 terminates the first embryonic genome activation event in mouse two-cell embryos and contributes to a transcriptionally repressive state

Abstract

Embryonic genome activation (EGA) in mammals begins with transient expression of a large group of genes (EGA1). Importantly, entry into and exit from the 2C/EGA state is essential for viability. <i>Dux</i> family member genes play an integral role in EGA1 by activating other EGA marker genes such as <i>Zscan4</i> family members. We previously reported that structural maintenance of chromosomes flexible hinge domain-containing protein 1 (<i>Smchd1</i>) is expressed at the mRNA and protein levels in mouse oocytes and early embryos and that elimination of <i>Smchd1</i> expression inhibits inner cell mass formation, blastocyst formation and hatching, and term development. We extend these observations here by showing that siRNA knockdown of <i>Smchd1</i> in zygotes results in overexpression of <i>Dux</i> and <i>Zscan4</i> in two-cell embryos, with continued overexpression of <i>Dux</i> at least through the eight-cell stage as well as prolonged expression of <i>Zscan4</i>. These results are consistent with a role for SMCHD1 in promoting exit from the EGA1 state and establishing SMCHD1 as a maternal effect gene and the first chromatin regulatory factor identified with this role. Additionally, bioinformatics analysis reveals that SMCHD1 also contributes to the creation of a transcriptionally repressive state to allow correct gene regulation.