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Peraki, I.* ; Zhang, L.* ; Botskaris, D.* ; Stagaki, M.* ; Deligiannis, I.K. ; Kontaki, H.* ; Deligianni, E.* ; Giannoulakis, I.* ; Hazapis, O.* ; Lavigne, M.* ; Martinez Jimenez, C.P. ; Talianidis, I.*

Setdb1 safeguards proper differentiation of adult intestinal stem cells by controlling chromatin accessibility and transcriptome variability.

iScience 29:116731 (2026)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
The histone methylase Setdb1 plays a pivotal role in embryonic stem cell maintenance and developmental lineage specification. However, its function in adult stem cells remains elusive. Here we show that the conditional inactivation of Setdb1 in Lgr5+ intestinal stem cells alters the transcriptional programs of the progeny cell types and results in increased cell-to-cell transcriptional variability. Loss of Setdb1 blocked differentiation toward the absorptive enterocyte lineage, while the secretory cell types were only marginally affected due to the activation of alternative developmental trajectories. Setdb1 inactivation did not affect global H3K9 methylation at large heterochromatin domains but led to altered distribution of transposase-accessible chromatin regions, aberrant exposure of transcription factor binding sites, and premature activation of differentiation-specific genes. The results demonstrate that Setdb1 regulates intestinal stem cell differentiation by fine-tuning chromatin accessibility in open euchromatin regions, thereby controlling transcriptional variability between cells.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Chromatin ; Stem Cell ; Heterochromatin ; Histone ; Cellular Differentiation ; Transcriptome ; Transcription Factor ; Euchromatin ; Polycomb-group Proteins ; Embryonic Stem Cell
ISSN (print) / ISBN 2589-0042
e-ISSN 2589-0042
Journal iScience
Quellenangaben Volume: 29, Issue: 8, Pages: , Article Number: 116731 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam ; Bosten ; London ; New York ; Oxford ; Paris ; Philadelphia ; San Diego ; St. Louis
Reviewing status Peer reviewed
Institute(s) Helmholtz Pioneer Campus (HPC)