Deep conservation of the enhancer regulatory code in animals

Abstract

Interactions of transcription factors (TFs) with DNA regulatory sequences, known as enhancers, specify cell identity during animal development. Unlike TFs, the origin and evolution of enhancers has been difficult to trace. We drove zebrafish and mouse developmental transcription using enhancers from an evolutionarily distant marine sponge. Some of these sponge enhancers are located in highly conserved microsyntenic regions, including an Islet enhancer in the Islet-Scaper region. We found that Islet enhancers in humans and mice share a suite of TF binding motifs with sponges, and that they drive gene expression patterns similar to those of sponge and endogenous Islet enhancers in zebrafish. Our results suggest the existence of an ancient and conserved, yet flexible, genomic regulatory syntax that has been repeatedly co-opted into cell type–specific gene regulatory networks across the animal kingdom.

A gene desert required for regulatory control of pleiotropicShox2expression and embryonic survival

“…Within this context, future comparative studies should search for deeply conserved orthologs of SHOX and SHOX2 enhancers in basal chordates such as amphioxus, which express their single Shox gene in the developing hindbrain 62 . The recent identification of orthologous Islet gene enhancers in sponges and vertebrates 63 demonstrate the promise of such an approach.…”

Heart Enhancers: Development and Disease Control at a Distance

“…A recent and striking example is a sponge Islet enhancer, which drives expression that overlaps endogenous islet gene (isl2a) expression in zebrafish, despite the absence of homologous sequence in the vertebrate genomes. Nevertheless, enhancers with similar TFBS compositions can be found in human and mouse ISLET/Islet regions and their activities resemble that of the sponge enhancer in zebrafish (Wong et al, 2020). A similar strategy based on motif composition also identified conserved brain enhancers between chordates and hemichordates, which would not have been detected by sequence alignment alone (Yao et al, 2016).…”

“…This assumption is supported by the genome-wide identification of conserved non-coding elements (CNEs) and the following discoveries that many CNEs work as developmental enhancers (Nobrega et al, 2003;Bejerano et al, 2004;Johnson et al, 2004;de la Calle-Mustienes et al, 2005;Shin et al, 2005;Woolfe et al, 2005;Pennacchio et al, 2006). Substantial work using a variety of approaches including transitive alignment (Hiller et al, 2013;Braasch et al, 2016), ancestral reconstruction (Hiller et al, 2013), and conserved microsynteny (Irimia et al, 2012;Clément et al, 2020;Wong et al, 2020) have further enhanced our ability to detect more distantly related conserved non-coding elements.…”

GWAS associated Variants, Non-genetic Factors, and Transient Transcriptome in Multiple Sclerosis Etiopathogenesis: a Colocalization Analysis

“…Moreover, new gene regulatory models may emerge from this approach in order to better evaluate the meaning of GWAS in complex traits and the impact of the enhancer transcription, 47 which was recently reported as an ancient and conserved, yet flexible, genomic regulatory syntax. 54…”