Genome-wide errant targeting by Hairy.

Kurtulus Kok,Li M Li,Ahmet Ay,David N Arnosti

doi:10.7554/elife.06394

Abstract

Metazoan transcriptional repressors regulate chromatin through diverse histone modifications. Contributions of individual factors to the chromatin landscape in development is difficult to establish, as global surveys reflect multiple changes in regulators. Therefore, we studied the conserved Hairy/Enhancer of Split family repressor Hairy, analyzing histone marks and gene expression in Drosophila embryos. This long-range repressor mediates histone acetylation and methylation in large blocks, with highly context-specific effects on target genes. Most strikingly, Hairy exhibits biochemical activity on many loci that are uncoupled to changes in gene expression. Rather than representing inert binding sites, as suggested for many eukaryotic factors, many regions are targeted errantly by Hairy to modify the chromatin landscape. Our findings emphasize that identification of active cis-regulatory elements must extend beyond the survey of prototypical chromatin marks. We speculate that this errant activity may provide a path for creation of new regulatory elements, facilitating the evolution of novel transcriptional circuits.

Highlights

Metazoan transcriptional circuitry features activation and repression signals that constitute robust regulatory networks important for the unfolding of developmental programs
The long-range effect has been proposed to be due to the recruitment of the corepressor Groucho (Gro), that can oligomerize to spread over large areas of the genome, and colocalization of HDAC to the target genes resulting in deacetylation of specific lysine residues in histones H3
To study transcriptional repression at the genome-wide level at this important developmental stage, we profiled changes in transcriptome, epigenome and RNA polymerase II (Pol II) binding regulated by Hairy in the blastoderm embryo using an inducible system as described previously to capture direct effects with high temporal resolution (Li and Arnosti, 2011) (Figure 1A)

Summary

Introduction

Metazoan transcriptional circuitry features activation and repression signals that constitute robust regulatory networks important for the unfolding of developmental programs. Short-range acting proteins Snail and Knirps interfere with transcription only when their cognate binding sites are located within close range of the activator binding sites (Gray and Levine, 1996) These proteins interact with evolutionarily conserved corepressors that possess chromatin modifying activities (Nibu et al, 1998; Payankaulam and Arnosti, 2009). These same cofactors are recruited by another class of repressors, the long-range transcriptional repressors, exemplified by the Hairy factor (Paroush et al, 1994; Barolo and Levine, 1997; Poortinga et al, 1998). The long-range effect has been proposed to be due to the recruitment of the corepressor Groucho (Gro), that can oligomerize to spread over large areas of the genome, and colocalization of HDAC to the target genes resulting in deacetylation of specific lysine residues in histones H3

Methods

Results

Conclusion