1. Cooperative Binding of Transcription Factors Orchestrates Reprogramming
- Author
-
Constantinos Chronis, Petko Fiziev, Kathrin Plath, Bernadett Papp, Giancarlo Bonora, Stefan Butz, Shan Sabri, and Jason Ernst
- Subjects
0301 basic medicine ,Somatic cell ,Sox2 ,Oct4 ,Medical and Health Sciences ,Mice ,0302 clinical medicine ,Histone code ,Regulatory Elements, Transcriptional ,Genetics ,Silencer Elements ,Biological Sciences ,Cellular Reprogramming ,Klf4 ,Chromatin ,Cell biology ,Histone Code ,KLF4 ,Transcriptional ,Reprogramming ,Proto-Oncogene Proteins c-fos ,induced pluripotent stem cells ,Kruppel-Like Transcription Factors ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Kruppel-Like Factor 4 ,SOX2 ,transcription factors ,Silencer Elements, Transcriptional ,Animals ,Enhancer ,Transcription factor ,SOXB1 Transcription Factors ,Human Genome ,fungi ,reprogramming ,Fibroblasts ,pluripotency ,Stem Cell Research ,Regulatory Elements ,collaborative binding ,030104 developmental biology ,enhancers ,Generic health relevance ,Octamer Transcription Factor-3 ,030217 neurology & neurosurgery ,Developmental Biology ,Transcription Factors - 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 andwith stage-specific TFs direct both somatic-enhancer inactivation and pluripotency-enhancer selection to drive reprogramming.
- Published
- 2016