An ancient yet flexible cis-regulatory architecture allows localized Hedgehog tuning by patched/Ptch1.

Elife
Authors
Abstract

The Hedgehog signaling pathway is part of the ancient developmental-evolutionary animal toolkit. Frequently co-opted to pattern new structures, the pathway is conserved among eumetazoans yet flexible and pleiotropic in its effects. The Hedgehog receptor, Patched, is transcriptionally activated by Hedgehog, providing essential negative feedback in all tissues. Our locus-wide dissections of the cis-regulatory landscapes of fly patched and mouse Ptch1 reveal abundant, diverse enhancers with stage- and tissue-specific expression patterns. The seemingly simple, constitutive Hedgehog response of patched/Ptch1 is driven by a complex regulatory architecture, with batteries of context-specific enhancers engaged in promoter-specific interactions to tune signaling individually in each tissue, without disturbing patterning elsewhere. This structure-one of the oldest cis-regulatory features discovered in animal genomes-explains how patched/Ptch1 can drive dramatic adaptations in animal morphology while maintaining its essential core function. It may also suggest a general model for the evolutionary flexibility of conserved regulators and pathways.

Year of Publication
2016
Journal
Elife
Volume
5
Date Published
2016 May 05
ISSN
2050-084X
URL
DOI
10.7554/eLife.13550
PubMed ID
27146892
PubMed Central ID
PMC4887206
Links
Grant list
R01 DC014428 / DC / NIDCD NIH HHS / United States
R01 NS033642 / NS / NINDS NIH HHS / United States
R01 GM076509 / GM / NIGMS NIH HHS / United States
T32 HD007505 / HD / NICHD NIH HHS / United States
T32 GM007315 / GM / NIGMS NIH HHS / United States