Histone H3K27ac separates active from poised enhancers and predicts developmental state

TLDR

Developmental programs are governed by transcription factors and chromatin regulators that epigenetically modify the genome, and enhancer-associated histone marks and transcription factors shape cell state and differentiation potential, but the link between these modifications and gene expression or developmental state remains unclear. The study interrogates the epigenetic landscape of enhancer elements in mouse embryonic stem cells and several adult tissues. The authors profile histone modifications across these cell types to map enhancer landscapes. They find that H3K27ac distinguishes active enhancers from H3K4me1‑only poised enhancers, indicating fewer active enhancers than previously anticipated, that poised enhancer networks reveal unrealized developmental programs, and that enhancers reset during nuclear reprogramming.

Abstract

Developmental programs are controlled by transcription factors and chromatin regulators, which maintain specific gene expression programs through epigenetic modification of the genome. These regulatory events at enhancers contribute to the specific gene expression programs that determine cell state and the potential for differentiation into new cell types. Although enhancer elements are known to be associated with certain histone modifications and transcription factors, the relationship of these modifications to gene expression and developmental state has not been clearly defined. Here we interrogate the epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse. We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements containing H3K4me1 alone. This indicates that the amount of actively used enhancers is lower than previously anticipated. Furthermore, poised enhancer networks provide clues to unrealized developmental programs. Finally, we show that enhancers are reset during nuclear reprogramming.