SALL4 controls cell fate in response to DNA base composition.
DNA base composition
SALL4
differentiation
embryonic stem cells
gene regulation
pluripotency
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 02 2021
18 02 2021
Historique:
received:
29
07
2020
revised:
23
10
2020
accepted:
25
11
2020
pubmed:
7
1
2021
medline:
3
3
2021
entrez:
6
1
2021
Statut:
ppublish
Résumé
Mammalian genomes contain long domains with distinct average compositions of A/T versus G/C base pairs. In a screen for proteins that might interpret base composition by binding to AT-rich motifs, we identified the stem cell factor SALL4, which contains multiple zinc fingers. Mutation of the domain responsible for AT binding drastically reduced SALL4 genome occupancy and prematurely upregulated genes in proportion to their AT content. Inactivation of this single AT-binding zinc-finger cluster mimicked defects seen in Sall4 null cells, including precocious differentiation of embryonic stem cells (ESCs) and embryonic lethality in mice. In contrast, deletion of two other zinc-finger clusters was phenotypically neutral. Our data indicate that loss of pluripotency is triggered by downregulation of SALL4, leading to de-repression of a set of AT-rich genes that promotes neuronal differentiation. We conclude that base composition is not merely a passive byproduct of genome evolution and constitutes a signal that aids control of cell fate.
Identifiants
pubmed: 33406384
pii: S1097-2765(20)30888-1
doi: 10.1016/j.molcel.2020.11.046
pmc: PMC7895904
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Sall4 protein, mouse
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
845-858.e8Subventions
Organisme : Wellcome Trust
ID : 200898/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203149
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107930/Z/15/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 101489/Z/13/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 200898
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800401
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 092076
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107930
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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