title: 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.
authors.affiliation: 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.
authors.forename: David S
authors.initials: DS
authors.lastname: Lorberbaum
authors.affiliation: 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.
authors.forename: Andrea I
authors.initials: AI
authors.lastname: Ramos
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States.|The Jackson Laboratory, Bar Harbor, United States.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Peterson
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Carpenter
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Parker
authors.affiliation: 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.
authors.forename: Sandip
authors.initials: S
authors.lastname: De
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Hillers
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 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.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Blake
authors.affiliation: 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.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nishi
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States.
authors.forename: Matthew R
authors.identifier: 0000-0001-8690-5633
authors.initials: MR
authors.lastname: McFarlane
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Ason Cy
authors.initials: AC
authors.lastname: Chiang
authors.affiliation: 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.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Kassis
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Benjamin L
authors.identifier: 0000-0003-2323-8313
authors.initials: BL
authors.lastname: Allen
authors.affiliation: 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.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Scott
authors.identifier: 0000-0002-8406-3716
authors.initials: S
authors.lastname: Barolo
mesh_terms: D000818:Animals; D002460:Cell Line; D004330:Drosophila; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D000072081:Patched-1 Receptor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse
keywords: 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