Colomer-Boronat, A.; Knol, L. I.; Peris, G.; Sanchez, L.; Peluso, S.; Tristan-Ramos, P.; Gazquez-Gutierrez, A.; Chin, P.; Gordon, K.; Barturen, G.; Hill, R. E.; Garcia-Perez, J. L.; Ivens, A.; Macias, S.; Heras, S. R.

The 22q11.2 deletion syndrome (22qDS) is caused by a microdeletion in chromosome 22, including DGCR8, an essential gene for miRNA production. The contribution of human DGCR8 hemizygosity to the disease is still unclear. In this study, we generated two human pluripotent cell models containing a single functional DGCR8 allele to elucidate its role on 22qDS. DGCR8+/- cells show increased apoptosis as well as self-renewal and differentiation defects in both the naive and primed states. The expression of primate-specific miRNAs was largely affected, due to impaired miRNA processing and chromatin accessibility. DGCR8+/- cells also displayed a pronounced reduction in human endogenous retrovirus class H (HERVH) expression, a primate-specific retroelement essential for pluripotency maintenance. Importantly, the reintroduction of primate-specific miRNAs as well as the miR-371-3 cluster rescued the cellular and molecular phenotypes of DGCR8+/- cells. Our results suggest that DGCR8 is haploinsufficient in humans and that miRNAs and transposable elements may have co-evolved in primates as part of an essential regulatory network to maintain stem cell identity.