DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects Colomer-Boronat, Ana Peris Ripollés, Guillermo Sánchez, Laura Tristán Ramos, Pablo Gázquez Gutiérrez, Ana Barturen, Guillermo Sánchez-Luque, Franscisco J. García Pérez, José Luis Macías, Sara Rodríguez Heras, Sara This work was supported by Ministerio de Ciencia e Innovación MCIN/AEI/10.13039/501100011033 [PID2020-115033RB-I00, PEJ2018-003280-A, RYC-2016-21395, and CNS2023-145402] ; ESF; Career Integration Grant—Marie Curie [FP7-PEOPLE-2011-CIG-303812]; FEDER/Consejería de Transformación Económica, Industria, Conocimiento y Universidades (Junta de Andalucía) [PY20_00619 and A-CTS-28_UGR20 grants]; donation to ‘Aula de estudios 22qDS’ (to S.R.H.); Wellcome Trust grants [221737/Z/20/Z and 107665/Z/15/Z]; the Royal Society grant [RGS\R1\191368]; the Wellcome Trust iTPA [PIII021] (to S.M.); MRC—Precision Medicine fellowship (to L.K.); Darwin Trust fellowship (to P.C.); Ministerio de Ciencia e Innovación, Agencia estatal de Investigación [PRE2021-098878] (to A.G.-G.); European Research Council (ERC) [ERC-Consolidator ERC-STG-2012-309433]; the Government of Spain [Ministerio de Ciencia e Innovación SAF2017-89745-R and PID2021-128934NB-I00]; Junta de Andalucia [P12-CTS-2256 and P18-RT-5067]; a private donation from Ms Francisca Serrano (Trading y Bolsa para Torpes, Granada, Spain) (to J.L.G.P.); and the Agencia Estatal de Investigación [RYC2021-031920-I, PID2022-143185NA-I00 and CNS2022-136033] (to F.J.S.L.). Funding to pay the Open Access publication charges for this article was provided by Universidad de Granada/CBUA. The 22q11.2 deletion syndrome (22qDS) is a human disorder where the majority of clinical manifestations originate during embryonic development. 22qDS is caused by a microdeletion in one chromosome 22, including DGCR8, an essential gene for miRNA production. However, the impact of DGCR8 hemizygosity on human development is still unclear. In this study, we generated two human pluripotent cell models containing a single functional DGCR8 allele to elucidate its role on early development. DGCR8+/- human embryonic stem cells (hESCs) showed increased apoptosis as well as self-renewal and differentiation defects in both the naïve and primed states. The expression of primate-specific miRNAs was largely affected, due to impaired miRNA processing and chromatin accessibility. DGCR8+/- hESCs also displayed a pronounced reduction in human endogenous retrovirus class H (HERVH) expression, a primate-specific retroelement essential for pluripotency maintenance. The reintroduction of miRNAs belonging to the primate-specific C19MC cluster as well as the miR-371-3 cluster rescued the defects of DGCR8+/- cells. Mechanistically, downregulation of HERVH by depletion of primate-specific miRNAs was mediated by KLF4. Altogether, we show 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 2025-03-27T11:36:27Z 2025-03-27T11:36:27Z 2025-03 journal article Colomer-Boronat et al. Primate-specific regulation by DGCR8. Nucleic Acids Research, 2025, 53, gkaf197. https://doi.org/10.1093/nar/gkaf197 https://hdl.handle.net/10481/103305 10.1093/nar/gkaf197 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Oxford University Press