<i>DGCR8</i> haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects
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 microRNA (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 in 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.
Authors
- José L. García-Pérez (ORCID: https://orcid.org/0000-0002-8132-9849)
- Lisanne I Knol (ORCID: https://orcid.org/0000-0002-8975-0398)
- G. Peris (ORCID: https://orcid.org/0000-0003-2010-7844)
- Katrina Gordon (ORCID: https://orcid.org/0000-0002-2498-9605)
- Sara R. Heras (ORCID: https://orcid.org/0000-0003-1677-7685)
- Robert E. Hill (ORCID: https://orcid.org/0000-0003-2848-1080)
- Guillermo Barturen (ORCID: https://orcid.org/0000-0003-2103-1028)
- Ana Gázquez-Gutiérrez (ORCID: https://orcid.org/0000-0001-5868-3148)
- Pablo Tristán-Ramos (ORCID: https://orcid.org/0000-0001-5368-0466)
- Alasdair Ivens (ORCID: https://orcid.org/0000-0002-0112-3876)
- Silvia Peluso (ORCID: https://orcid.org/0000-0003-1803-5300)
- Francisco J. Sánchez‐Luque (ORCID: https://orcid.org/0000-0003-1138-6124)
- Sara Macías (ORCID: https://orcid.org/0000-0002-0643-3494)
- Ana Colomer-Boronat (ORCID: https://orcid.org/0000-0003-2507-1748)
- Laura Sánchez (ORCID: https://orcid.org/0000-0003-2053-394X)
- P Chin (ORCID: https://orcid.org/0009-0008-7500-7254)
Institutions
- Universitat Jaume I (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Universidad de Granada (ES)
- Centre for Immunity, Infection and Evolution (GB)
- Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (ES)
- Instituto de Parasitología y Biomedicina "López - Neyra" (ES)
- Institute of Genetics and Cancer (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1093/nar/gkaf197
- Citations
- 7
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 6.55
Funders
- Esperantic Studies Foundation
- Wellcome Trust
- Consejería de Transformación Económica, Industria, Conocimiento y Universidades
- Royal Society
- Marie Curie
- Federación Española de Enfermedades Raras
- Ministerio de Ciencia e Innovación
- Universidad de Granada
- Darwin Trust of Edinburgh
- Musculoskeletal Research Center, Washington University in St. Louis
- Agencia Estatal de Investigación
- H2020 European Research Council