An ancient yet flexible cis-regulatory architecture allows localized Hedgehog tuning by patched/Ptch1
David S Lorberbaum,
Andrea I Ramos,
Kevin A Peterson,
Brandon S Carpenter,
David S Parker,
Sandip De,
Lauren E Hillers,
Victoria M Blake,
Yuichi Nishi,
Matthew R McFarlane,
Ason CY Chiang,
Judith A Kassis,
Benjamin L Allen,
Andrew P McMahon,
Scott Barolo
Affiliations
David S Lorberbaum
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
Andrea I Ramos
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
Kevin A Peterson
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States; The Jackson Laboratory, Bar Harbor, United States
Brandon S Carpenter
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
David S Parker
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
Sandip De
Program in Genomics of Differentiation, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Lauren E Hillers
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
Victoria M Blake
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States; Program in Genomics of Differentiation, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Yuichi Nishi
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
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
Ason CY Chiang
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
Judith A Kassis
Program in Genomics of Differentiation, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
Andrew P McMahon
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, 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.
