SALL4 controls cell fate in response to DNA base composition

Raphael Pantier, Kashyap Chhatbar, Timo Quante, Konstantina Skourti Stathaki, Justyna Cholewa-Waclaw, Grace Alston, Beatrice Alexander-Howden, Heng Yang Lee, Atlanta G. Cook, Cornelia G. Spruijt, Michiel Vermeulen, Jim Selfridge, Adrian P. Bird

Research output: Contribution to journalArticlepeer-review

Abstract

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 by product of genome evolution and constitutes a signal that aids control of cell fate.
Original languageEnglish
Pages (from-to)845-858
Number of pages14
JournalMolecular Cell
Volume81
Issue number4
Early online date5 Jan 2021
DOIs
Publication statusPublished - 18 Feb 2021

Keywords

  • DNA base composition
  • SALL4
  • gene regulation
  • differentiation
  • embryonic stem cells
  • pluripotency

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