Resf1 is required for normal placental development and configuration of trophoblast cell-specific heterochromatin [RNA-seq]

Resf1 (Retroelement silencing factor 1) is involved in retroelement silencing cooperated with H3K9 methyltransferase SETDB1 by regulating H3K9 methylation in mouse embryonic stem cells (mESCs). However, it remains unknown whether Resf1 functions in retroelement silencing in vivo, and has a role in development. To address this question, we established Resf1-deficient mice. The Resf1-deficient mice show developmental delay, partial embryonic lethality, and placental abnormalities. Remarkably, retroelements are also upregulated in the Resf1-deficient placenta, and this upregulation of retroelements correlates with elevated expression of nearby genes. Additionally, to determine whether Resf1 functions within the trophoblast lineage—given the heterogeneous cellular composition of the placenta—we established Resf1-deficient trophoblast stem cell (TSC) lines. Both undifferentiated TSCs and differentiated TSCs (D-TSCs) display increased retroelement expression along with elevated levels of genes associated with placental development. Furthermore, Resf1-deficient TSCs exhibit compromised maintenance of H3K9me3 domains, leading to instability. In summary, our findings illuminate Resf1's multifaceted roles beyond retroelement silencing, uncovering its significance in developmental processes and its intricate involvement in trophoblast lineage regulation.