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Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Mayer, Daniela 
Stadler, Michael B 
Rittirsch, Melanie 
Hess, Daniel 
Lukonin, Ilya 

Abstract

Developmental cell fate specification is a unidirectional process that can be reverted in response to injury or experimental reprogramming. Whether differentiation and de-differentiation trajectories intersect mechanistically is unclear. Here, we performed comparative screening in lineage-related mouse naïve embryonic stem cells (ESCs) and primed epiblast stem cells (EpiSCs), and identified the constitutively expressed zinc finger transcription factor (TF) Zfp281 as a bidirectional regulator of cell state interconversion. We showed that subtle chromatin binding changes in differentiated cells translate into activation of the histone H3 lysine 9 (H3K9) methyltransferase Ehmt1 and stabilization of the zinc finger TF Zic2 at enhancers and promoters. Genetic gain-of-function and loss-of-function experiments confirmed a critical role of Ehmt1 and Zic2 downstream of Zfp281 both in driving exit from the ESC state and in restricting reprogramming of EpiSCs. Our study reveals that cell type-invariant chromatin association of Zfp281 provides an interaction platform for remodeling the cis-regulatory network underlying cellular plasticity.

Description

Keywords

cell state transition, cellular plasticity, differentiation, pluripotency, reprogramming, Animals, Cell Differentiation, Cells, Cultured, Chromatin, Gene Expression Regulation, Histone-Lysine N-Methyltransferase, Mice, Mouse Embryonic Stem Cells, Pluripotent Stem Cells, Transcription Factors

Journal Title

EMBO J

Conference Name

Journal ISSN

0261-4189
1460-2075

Volume Title

39

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
MRC (G1100526)