Abstract
Enhancer of Rudimentary Homolog (ERH) is an evolutionarily conserved protein originally characterized in fission yeast1 and recently shown to maintain H3K9me3 in human fibroblasts2. Here, we find that ERH depletion in fibroblasts reverts the H3K9me3 landscape to an embryonic stem cell (ESC) state and enables activation of naïve and pluripotency genes and transposable elements during induced pluripotent stem cell (iPSC) reprogramming. We find that ERH similarly 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 naïve 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 fundamental role for ERH in cell fate specification via the initiation and maintenance of early developmental gene repression.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵6 Lead contact
This version of the manuscript has been restructured to better describe and contextualize key findings. Additionally, this revision includes new results investigating the mechanism of ERH chromatin recruitment and cell type specific interactions with RNA binding proteins.
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE268961
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE268901
Data availability
RNA-seq and CUT&RUN datasets collected in this study have been deposited in the GEO of NCBI and are publicly available as of the date of publication. Accession numbers are listed in the Methods. GEO reviewer tokens for accessing the data while it remains in private status are for RNA-seq GSE268901 (wbsvkukqhzobpan), and for CUT&RUN GSE268961 (qngpsiywdvyfjyj).
