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Antonio Urrutia, G.* ; Ramachandran, H.* ; Cauchy, P.* ; Boo, K.* ; Ramamoorthy, S.* ; Boller, S.* ; Dogan, E.* ; Clapes, T.* ; Trompouki, E.* ; Torres-Padilla, M.E. ; Palvimo, J.J.* ; Pichler, A.* ; Grosschedl, R.*

ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation.

Genes Dev. 35, 1142-1160 (2021)
Publ. Version/Full Text DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
The establishment of cell fates involves alterations of transcription factor repertoires and repurposing of transcription factors by post-translational modifications. In embryonic stem cells (ESCs), the chromatin organizers SATB2 and SATB1 balance pluripotency and differentiation by activating and repressing pluripotency genes, respectively. Here, we show that conditional Satb2 gene inactivation weakens ESC pluripotency, and we identify SUMO2 modification of SATB2 by the E3 ligase ZFP451 as a potential driver of ESC differentiation. Mutations of two SUMO-acceptor lysines of Satb2 (Satb2 K R ) or knockout of Zfp451 impair the ability of ESCs to silence pluripotency genes and activate differentiation-associated genes in response to retinoic acid (RA) treatment. Notably, the forced expression of a SUMO2-SATB2 fusion protein in either Satb2 K R or Zfp451 -/- ESCs rescues, in part, their impaired differentiation potential and enhances the down-regulation of Nanog The differentiation defect of Satb2 K R ESCs correlates with altered higher-order chromatin interactions relative to Satb2 wt ESCs. Upon RA treatment of Satb2 wt ESCs, SATB2 interacts with ZFP451 and the LSD1/CoREST complex and gains binding at differentiation genes, which is not observed in RA-treated Satb2 K R cells. Thus, SATB2 SUMOylation may contribute to the rewiring of transcriptional networks and the chromatin interactome of ESCs in the transition of pluripotency to differentiation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Es Cell ; Lsd1 ; Satb1 ; Satb2 ; Sumo2 ; Zfp451 ; Differentiation ; Pluripotency; Binding-protein; Naive Pluripotency; Read Alignment; Chromatin; Gene; Nanog; Expression; Genome; Repression; Specification
ISSN (print) / ISBN 0890-9369
e-ISSN 1549-5477
Quellenangaben Volume: 35, Issue: 15-16, Pages: 1142-1160 Article Number: , Supplement: ,
Publisher Cold Spring Harbor Laboratory Press
Publishing Place 1 Bungtown Rd, Cold Spring Harbor, Ny 11724 Usa
Reviewing status Peer reviewed
Grants Marie Sklodowska-Curie grant of the European Union's Horizon 2020 research and innovation program
Wilhelm Sanders Stiftung
Academy of Finland
German Research Foundation
Max Planck Society (MPS)