RT Journal Article
SR Electronic
T1 Identification of X-chromosomal genes that drive global X-dosage effects in mouse embryonic stem cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.09.983544
DO 10.1101/2020.03.09.983544
A1 Oriana Genolet
A1 Anna A. Monaco
A1 Ilona Dunkel
A1 Michael Boettcher
A1 Edda G. Schulz
YR 2021
UL http://biorxiv.org/content/early/2021/01/18/2020.03.09.983544.abstract
AB X-chromosomal genes contribute to sex differences, in particular during early development, when both X chromosomes are active in females. Here, double X-dosage shifts female pluripotent cells towards the naive stem cell state by increasing pluripotency factor expression, inhibiting the differentiation-promoting MAP kinase (MAPK) signalling pathway and delaying differentiation. To identify the genetic basis of these sex differences, we have performed a series of CRISPR knockout screens in murine embryonic stem cells to comprehensively identify X-linked genes that cause the female pluripotency phenotype. We found multiple genes that act in concert, among which Klhl13 plays a central role. We show that this E3 ubiquitin ligase substrate adaptor protein promotes pluripotency factor expression, delays differentiation and represses MAPK target genes, and we identify putative substrates. We thus elucidate the mechanisms that drive sex-induced differences in pluripotent cells with implications for gender medicine in the context of induced pluripotent stem cell based therapies.Competing Interest StatementThe authors have declared no competing interest.