An ancient yet flexible cis-regulatory architecture allows localized Hedgehog tuning by patched/Ptch1
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.
Additional details
Funding
- National Institute of General Medical Sciences
- T32-GM007315
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Intramural Research Program
- American Heart Association
- 11SDG638000
- National Science Foundation
- MCB-1157800
- National Institute on Deafness and Other Communication Disorders
- R01 DC014428
- National Institute of General Medical Sciences
- R01 GM076509
- National Institute of Neurological Disorders and Stroke
- R01 NS033642