Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2025
Erindi/veggspjald / Talk/poster E91
Höfundar / Authors: Katrín Möller (1), Afrooz Razi (2), Stefán Pétursson (1), Kasper D. Hansen (2), Hans T. Björnsson (1, 3)
Starfsvettvangur / Affiliations: 1. Louma G. Laboratory of Epigenetic Research, Faculty of Medicine, University of Iceland; Reykjavík, Iceland. 2. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, USA. 3. Department of Genetics and Molecular Medicine, Landspítali University Hospital; Reykjavík, Iceland.
Kynnir / Presenter: Katrín Möller
The epigenetic machinery (EM) includes >300 proteins that shape chromatin and affect gene expression. More than 85 disorders are associated with loss of EM genes, collectively called the Mendelian disorders of the epigenetic machinery (MDEMs), which commonly present with phenotypes such as intellectual disability (ID) and other neurological dysfunction. This suggests a central role for the EM in brain development but the shared mechanisms underlying these features are poorly understood. To address this, we investigated the consequences of disrupting 60 EM genes in a neurodevelopmental model. Murine neuronal progenitor cells (NPC) were isolated, EM genes knocked out in a pooled CRISPR screen, and the NPCs differentiated in vitro. Single-cell RNA-seq was performed at the NPC stage and after 3, 6 and 12 days of differentiation. Our results reveal a convergence in transcriptional changes amongst many EM genes, with downstream targets enriched for autism and schitzophrenia risk genes. Several knockouts also altered lineage trajectories, e.g. loss of Crebbp biased cells toward immature neurons, while loss of Setd1b promoted astrocytic fate. Notably, some of these effects appear linked to abnormal p53 regulation, highlighting a potential shared disrupted pathway. ID affects up to 2% of the population, and the MDEM are a large group of genetically determined ID. Our findings provide new insight into the biology of MDEMs, and may open up therapeutic strategies for MDEMs and other caus