Beyond the ENCODE project: using genomics and epigenomics strategies to study enhancer evolution

Abstract

The complex expression patterns observed for many genes are often regulated by distal transcription enhancers. Changes in the nucleotide sequences of enhancers may therefore lead to changes in gene expression, representing a central mechanism by which organisms evolve. With the development of the experimental technique of chromatin immunoprecipitation (ChIP), in which discrete regions of the genome bound by specific proteins can be identified, it is now possible to identify transcription factor binding events (putative cis -regulatory elements) in entire genomes. Comparing protein–DNA binding maps allows us, for the first time, to attempt to identify regulatory differences and infer global patterns of change in gene expression across species. Here, we review studies that used genome-wide ChIP to study the evolution of enhancers. The trend is one of high divergence of cis -regulatory elements between species, possibly compensated by extensive creation and loss of regulatory elements and rewiring of their target genes. We speculate on the meaning of the differences observed and discuss that although ChIP experiments identify the biochemical event of protein–DNA interaction, it cannot determine whether the event results in a biological function, and therefore more studies are required to establish the effect of divergence of binding events on species-specific gene expression.

GR and LSD1/KDM1A-Targeted Gene Activation Requires Selective H3K4me2 Demethylation at Enhancers

“…We find that GR, and many other NRs, can modulate KDM1A activity to protect H3K4me1. Surveying the steady-state genome for enhancer marks finds H3K4me1 and H3K27ac (Calo and Wysocka, 2013;Sakabe and Nobrega, 2013). Our data are consistent with this as H3K4me1 remains enriched after GR activation and KDM1A recruitment.…”

Ever-Changing Landscapes: Transcriptional Enhancers in Development and Evolution

“…p300, Mediator, BRG1) or their enzymatic products (e.g. H3K27ac, catalyzed by p300/CBP or H3K4me1, catalyzed by MLL3/4) can be mapped using ChIP-seq (for reviews on enhancer chromatin signatures and epigenomic annotation strategies see (Calo and Wysocka, 2013; Sakabe and Nobrega, 2013; Whitaker et al, 2015)).…”

Expression of regulatory genes in the embryonic brain of a lizard and implications for understanding pallial organization and evolution

“…Basically, the brain develops under the influence of perfectly orchestrated networks of developmental regulatory genes, which determine much of its mature structure and function (reviewed by Medina and Abellán, ). Variations in the expression of these regulatory genes, often determined by permanent modifications at their noncoding regulatory region (including enhancers) and/or the factors/cofactors that bind to it, are behind evolutionary changes (Carroll, ; Carroll, Grenier, & Weatherbee, ; Davidson, ; Sakabe & Nobrega, ). Both the coding region and the regulatory region of genes active at early stages of forebrain development show a high level of sequence conservation (thus, there is a high constraint against variation), but the level of constraint appears to decrease in the regulatory regions of genes active from mid‐gestation to adults (Capra, Erwin, McKinsey, Rubenstein, & Pollard, ; Nord, Pattabiraman, Visel, & Rubenstein, ).…”