title: Distal Limb Patterning Requires Modulation of cis-Regulatory Activities by HOX13.
abstract: The combinatorial expression of Hox genes along the body axes is a major determinant of cell fate and plays a pivotal role in generating the animal body plan. Loss of HOXA13 and HOXD13 transcription factors (HOX13) leads to digit agenesis in mice, but how HOX13 proteins regulate transcriptional outcomes and confer identity to the distal-most limb cells has remained elusive. Here, we report on the genome-wide profiling of HOXA13 and HOXD13 in vivo binding and changes of the transcriptome and chromatin state in the transition from the early to the late-distal limb developmental program, as well as in Hoxa13-/-; Hoxd13-/-limbs. Our results show that proper termination of the early limb transcriptional program and activation of the late-distal limb program are coordinated by the dual action of HOX13 on cis-regulatory modules.
authors.affiliation: Laboratory of Genetics and Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, QC H2W1R7, Canada. Electronic address: rushikesh.s.sheth@gmail.com.
authors.forename: Rushikesh
authors.initials: R
authors.lastname: Sheth
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Iros
authors.initials: I
authors.lastname: Barozzi
authors.affiliation: Department of Biochemistry, McGill University, 3649 Promenade Sir-William-Osler, Montréal, H3G0B1 QC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Langlais
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Osterwalder
authors.affiliation: Laboratory of Molecular Genetics, Institut de Recherches Cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, H2W1R7 QC, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Nemec
authors.affiliation: Department of Skeletal Biology, Shriners Hospital for Children, 3101 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Hanqian L
authors.initials: HL
authors.lastname: Carlson
authors.affiliation: Department of Skeletal Biology, Shriners Hospital for Children, 3101 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: H Scott
authors.initials: HS
authors.lastname: Stadler
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; School of Natural Sciences, University of California, Merced, CA 95340, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
authors.affiliation: Laboratory of Molecular Genetics, Institut de Recherches Cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, H2W1R7 QC, Canada; Department of Medicine, Université de Montréal, Montréal, H3T1J4 QC, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Drouin
authors.affiliation: Laboratory of Genetics and Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, QC H2W1R7, Canada; Department of Medicine, Université de Montréal, Montréal, H3T1J4 QC, Canada. Electronic address: marie.kmita@ircm.qc.ca.
authors.forename: Marie
authors.initials: M
authors.lastname: Kmita
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D005121:Extremities / Q000254:growth & development*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; C084118:Hoxd13 protein, mouse; D014157:Transcription Factors; C099959:homeobox protein HOXA13
keywords: ChIP-seq; HOX; Histone marks; Hoxa13; Hoxd13; chromatin state; digit; enhancer; limb development; transcriptional regulation