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Nat Cell Biol. 2019 Oct;21(10):1179-1190. doi: 10.1038/s41556-019-0390-6. Epub 2019 Sep 23.

KLF4 is involved in the organization and regulation of pluripotency-associated three-dimensional enhancer networks.

Author information

1
Sanford I Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
2
Department of Pathology, NYU School of Medicine, New York, NY, USA.
3
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Weill-Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD program, New York, NY, USA.
5
Department of Biochemistry, Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, NY, USA.
6
Skirball Institute of Biomolecular Medicine, Department of Cell Biology and Helen L. and Martin S. Kimmel Center for Biology and Medicine, NYU School of Medicine, New York, NY, USA.
7
Department of Pathology, NYU School of Medicine, New York, NY, USA. aristotelis.tsirigos@nyumc.org.
8
Laura and Isaac Perlmutter Cancer Center and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY, USA. aristotelis.tsirigos@nyumc.org.
9
Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY, USA. aristotelis.tsirigos@nyumc.org.
10
Sanford I Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. efa2001@med.cornell.edu.

Abstract

Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors, as is exemplified by reprogramming somatic cells to pluripotent stem cells through the expression of OCT4, KLF4, SOX2 and cMYC. How transcription factors orchestrate the complex molecular changes around their target gene loci remains incompletely understood. Here, using KLF4 as a paradigm, we provide a transcription-factor-centric view of chromatin reorganization and its association with three-dimensional enhancer rewiring and transcriptional changes during the reprogramming of mouse embryonic fibroblasts to pluripotent stem cells. Inducible depletion of KLF factors in PSCs caused a genome-wide decrease in enhancer connectivity, whereas disruption of individual KLF4 binding sites within pluripotent-stem-cell-specific enhancers was sufficient to impair enhancer-promoter contacts and reduce the expression of associated genes. Our study provides an integrative view of the complex activities of a lineage-specifying transcription factor and offers novel insights into the nature of the molecular events that follow transcription factor binding.

PMID:
31548608
DOI:
10.1038/s41556-019-0390-6
[Indexed for MEDLINE]

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