title: Cooperative Binding of Transcription Factors Orchestrates Reprogramming.
abstract: Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription factors (TFs), and chromatin states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that OSK predominantly bind active somatic enhancers early in reprogramming and immediately initiate their inactivation genome-wide by inducing the redistribution of somatic TFs away from somatic enhancers to sites elsewhere engaged by OSK, recruiting Hdac1, and repressing the somatic TF Fra1. Pluripotency enhancer selection is a stepwise process that also begins early in reprogramming through collaborative binding of OSK at sites with high OSK-motif density. Most pluripotency enhancers are selected later in the process and require OS and other pluripotency TFs. Somatic and pluripotency TFs modulate reprogramming efficiency when overexpressed by altering OSK targeting, somatic-enhancer inactivation, and pluripotency enhancer selection. Together, our data indicate that collaborative interactions among OSK and with stage-specific TFs direct both somatic-enhancer inactivation and pluripotency-enhancer selection to drive reprogramming.
authors.affiliation: David Geffen School of Medicine, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, Bioinformatics Program, Los Angeles, CA 90095, USA.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Chronis
authors.affiliation: David Geffen School of Medicine, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, Bioinformatics Program, Los Angeles, CA 90095, USA.
authors.forename: Petko
authors.initials: P
authors.lastname: Fiziev
authors.affiliation: David Geffen School of Medicine, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, Bioinformatics Program, Los Angeles, CA 90095, USA.
authors.forename: Bernadett
authors.initials: B
authors.lastname: Papp
authors.affiliation: David Geffen School of Medicine, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, Bioinformatics Program, Los Angeles, CA 90095, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Butz
authors.affiliation: David Geffen School of Medicine, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, Bioinformatics Program, Los Angeles, CA 90095, USA.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Bonora
authors.affiliation: David Geffen School of Medicine, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, Bioinformatics Program, Los Angeles, CA 90095, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Sabri
authors.affiliation: David Geffen School of Medicine, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, Bioinformatics Program, Los Angeles, CA 90095, USA. Electronic address: jason.ernst@ucla.edu.
authors.forename: Jason
authors.initials: J
authors.lastname: Ernst
authors.affiliation: David Geffen School of Medicine, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Jonsson Comprehensive Cancer Center, Bioinformatics Program, Los Angeles, CA 90095, USA. Electronic address: kplath@mednet.ucla.edu.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Plath
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D002843:Chromatin / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D042421:Histone Code; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D037941:Silencer Elements, Transcriptional; D014157:Transcription Factors / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D002843:Chromatin; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C000715468:Klf4 protein, mouse; C489428:Myc protein, mouse; C494174:Pou5f1 protein, mouse; C527783:Sox2 protein, mouse
keywords: Klf4; Oct4; Sox2; collaborative binding; enhancers; induced pluripotent stem cells; pluripotency; reprogramming; transcription factors