A cohesin-OCT4 complex mediates Sox enhancers to prime an early embryonic lineage.

Nesrine Abboud,Sonia Stefanovic,Henry Yang,Michel Pucéat,Emilye Hiriart,Anne-Claire Guénantin,Maria-Giovanna Gualazzi,Thomas Moore- Morris,Hudson Bezerra,Sylvia M Evans

doi:10.1038/ncomms7749

Abstract

Short- and long-scales intra- and inter-chromosomal interactions are linked to gene transcription, but the molecular events underlying these structures and how they affect cell fate decision during embryonic development are poorly understood. One of the first embryonic cell fate decisions (that is, mesendoderm determination) is driven by the POU factor OCT4, acting in concert with the high-mobility group genes Sox-2 and Sox-17. Here we report a chromatin-remodelling mechanism and enhancer function that mediate cell fate switching. OCT4 alters the higher-order chromatin structure at both Sox-2 and Sox-17 loci. OCT4 titrates out cohesin and switches the Sox-17 enhancer from a locked (within an inter-chromosomal Sox-2 enhancer/CCCTC-binding factor CTCF/cohesin loop) to an active (within an intra-chromosomal Sox-17 promoter/enhancer/cohesin loop) state. SALL4 concomitantly mobilizes the polycomb complexes at the Soxs loci. Thus, OCT4/SALL4-driven cohesin- and polycombs-mediated changes in higher-order chromatin structure mediate instruction of early cell fate in embryonic cells.

Highlights

Short- and long-scales intra- and inter-chromosomal interactions are linked to gene transcription, but the molecular events underlying these structures and how they affect cell fate decision during embryonic development are poorly understood
We reported that an increase in the level of expression of OCT4 in pluripotent embryonic stem cells (ESCs) either by nucleofection of a transgene or by challenging cells with the cardiogenic morphogen bone morphogenetic protein 2 (BMP2), a phenomenon that normally occurs during the early embryonic development, results in a switch of the POU transcription factor from the SOX-2 to the SOX-17 gene regulatory regions
By the use of single and sequential chromatin immunoprecicipitation (ChIP) assays as well as of chromosome conformation capture (3C) assays performed on chromatin of ESC-derived mesendoderm, we discovered that OCT4 targets the cohesin complex, and changes the higher-order chromatin structure at Sox-2 and Sox-17 loci to direct the fate of ESCs towards mesendoderm and cardiac mesoderm

Summary

Introduction

Short- and long-scales intra- and inter-chromosomal interactions are linked to gene transcription, but the molecular events underlying these structures and how they affect cell fate decision during embryonic development are poorly understood. We reported that an increase in the level of expression of OCT4 in pluripotent ESCs either by nucleofection of a transgene or by challenging cells with the cardiogenic morphogen bone morphogenetic protein 2 (BMP2), a phenomenon that normally occurs during the early embryonic development, results in a switch of the POU transcription factor from the SOX-2 to the SOX-17 gene regulatory regions. This phenomenon directs cells towards a mesendodermal lineage, and commits them towards a cardiac fate[16]. A greater insight into the molecular mechanisms underlying these cell-specific transcriptional genetic and epigenetic events will improve our knowledge of embryonic cardiogenesis and embryonic cell fate specification in general

Methods

Results

Conclusion