The BTB transcription factors ZBTB11 and ZFP131 maintain pluripotency by repressing pro-differentiation genes

Görkem Garipler, Congyi Lu, Alexis Morrissey, Lorena S. Lopez-Zepeda, Yingzhen Pei, Simon E. Vidal, Ana Paula Zen Petisco Fiore, Begüm Aydin, Matthias Stadtfeld, Uwe Ohler, Shaun Mahony, Neville E. Sanjana, Esteban O. Mazzoni

Research output: Contribution to journalArticlepeer-review

Abstract

In pluripotent cells, a delicate activation-repression balance maintains pro-differentiation genes ready for rapid activation. The identity of transcription factors (TFs) that specifically repress pro-differentiation genes remains obscure. By targeting ∼1,700 TFs with CRISPR loss-of-function screen, we found that ZBTB11 and ZFP131 are required for embryonic stem cell (ESC) pluripotency. ESCs without ZBTB11 or ZFP131 lose colony morphology, reduce proliferation rate, and upregulate transcription of genes associated with three germ layers. ZBTB11 and ZFP131 bind proximally to pro-differentiation genes. ZBTB11 or ZFP131 loss leads to an increase in H3K4me3, negative elongation factor (NELF) complex release, and concomitant transcription at associated genes. Together, our results suggest that ZBTB11 and ZFP131 maintain pluripotency by preventing premature expression of pro-differentiation genes and present a generalizable framework to maintain cellular potency.

Original languageEnglish (US)
Article number110524
JournalCell Reports
Volume38
Issue number11
DOIs
StatePublished - Mar 15 2022

Keywords

  • CRISPR screen
  • differentiation
  • embryonic stem cells
  • pluripotency
  • poised genes
  • transcription factors
  • Pluripotent Stem Cells/metabolism
  • Humans
  • Germ Layers/metabolism
  • Transcription Factors/genetics
  • Embryonic Stem Cells/metabolism
  • Animals
  • CRISPR-Cas Systems
  • Cell Differentiation/genetics
  • Mice

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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