ERH Enables Early Embryonic Differentiation and Overlays H3K9me3 Heterochromatin on a Cryptic Pluripotency H3K9me3 Landscape in Somatic Cells

Enhancer of Rudimentary Homolog (ERH) is an evolutionarily conserved protein originally characterized as promoting fission yeast heterochromatin1 and recently shown to maintain H3K9me3 heterochromatin in human fibroblasts2. Here, we find that ERH depletion in fibroblasts reverts the somatic cell H3K9me3 landscape of broad megabase size domains to an embryonic stem cell (ESC) state composed of mainly H3K9me3 peaks and enables activation of naive and pluripotency genes and transposable elements during induced pluripotent stem cell (iPSC) reprogramming. Concordantly, we find that ERH represses totipotent and alternative lineage programs during mouse preimplantation development and is required for proper segregation of the inner cell mass and trophectoderm cell lineages. During human ESC differentiation into germ layer lineages, ERH silences naive and pluripotency genes, transposable elements, and alternative lineage somatic genes. As in fission yeast, we find that mammalian ERH interacts with RNA-binding proteins to engage and repress its chromatin targets. Our findings reveal a conserved, fundamental role for ERH in cell fate specification via the initiation and maintenance of early developmental gene repression.