Hormone-dependent control of developmental timing through regulation of chromatin accessibility.

Christopher M Uyehara,Matthew J Niederhuber,Daniel J Mckay,Laura A Buttitta,Spencer L Nystrom,Mary Leatham-Jensen,Yiqin Ma

doi:10.1101/gad.298182.117

Abstract

Specification of tissue identity during development requires precise coordination of gene expression in both space and time. Spatially, master regulatory transcription factors are required to control tissue-specific gene expression programs. However, the mechanisms controlling how tissue-specific gene expression changes over time are less well understood. Here, we show that hormone-induced transcription factors control temporal gene expression by regulating the accessibility of DNA regulatory elements. Using the Drosophila wing, we demonstrate that temporal changes in gene expression are accompanied by genome-wide changes in chromatin accessibility at temporal-specific enhancers. We also uncover a temporal cascade of transcription factors following a pulse of the steroid hormone ecdysone such that different times in wing development can be defined by distinct combinations of hormone-induced transcription factors. Finally, we show that the ecdysone-induced transcription factor E93 controls temporal identity by directly regulating chromatin accessibility across the genome. Notably, we found that E93 controls enhancer activity through three different modalities, including promoting accessibility of late-acting enhancers and decreasing accessibility of early-acting enhancers. Together, this work supports a model in which an extrinsic signal triggers an intrinsic transcription factor cascade that drives development forward in time through regulation of chromatin accessibility.

Highlights

A defining feature of metazoan development is the organization of cells into tissues
One proposed mechanism to explain the distinctive power of master transcription factors is that they control where other transcription factors bind in the genome by regulating chromatin accessibility (Fakhouri et al 2010; Mullen et al 2011; Pham et al 2013)
We looked for enrichment of the motif for GAGA factor (GAF), a transcription factor often associated with transcriptional enhancers and open chromatin sites (Fuda et al 2015)

Summary

Introduction

A defining feature of metazoan development is the organization of cells into tissues. One proposed mechanism to explain the distinctive power of master transcription factors is that they control where other transcription factors bind in the genome by regulating chromatin accessibility (Fakhouri et al 2010; Mullen et al 2011; Pham et al 2013). Several lines of evidence support an important role for chromatin accessibility in transcription factor targeting in the genome Chief among these are the observations that only a small fraction of transcription factor DNAbinding motifs is occupied at a given point in time (Li et al 2008) and that many sites of transcription factor binding do not contain a recognizable DNA-binding motif (Kvon et al 2012). Regulation of chromatin accessibility plays a potentially pivotal role in controlling cell identity by determining where transcription factors can bind in the genome and the sets of genes that are expressed. Thyroid hormone controls the initiation and progression of metamorphosis in frogs (Shi 2013), whereas the sex hormones control the development of secondary sex traits during adolescence in mammals (Romeo 2003)

Methods

Results

Conclusion