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Elife. 2016 May 5;5. pii: e13550. doi: 10.7554/eLife.13550.

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

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Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States.
Program in Cellular and Molecular Biology, University Of Michigan Medical School, Ann Arbor, United States.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States.
The Jackson Laboratory, Bar Harbor, United States.
Program in Genomics of Differentiation, <italic>Eunice Kennedy Shriver</italic> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States.
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, United States.


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.


D. melanogaster; Hedgehog signaling; cis-regulatory elements; development; developmental biology; evolution of development (evo-devo); evolutionary biology; gene regulation; genomics; mouse; stem cells; transcriptional regulation

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