title: SOX9 modulates the expression of key transcription factors required for heart valve development.
abstract: Heart valve formation initiates when endothelial cells of the heart transform into mesenchyme and populate the cardiac cushions. The transcription factor SOX9 is highly expressed in the cardiac cushion mesenchyme, and is essential for heart valve development. Loss of Sox9 in mouse cardiac cushion mesenchyme alters cell proliferation, embryonic survival, and valve formation. Despite this important role, little is known about how SOX9 regulates heart valve formation or its transcriptional targets. Therefore, we mapped putative SOX9 binding sites by ChIP-Seq in E12.5 heart valves, a stage at which the valve mesenchyme is actively proliferating and initiating differentiation. Embryonic heart valves have been shown to express a high number of genes that are associated with chondrogenesis, including several extracellular matrix proteins and transcription factors that regulate chondrogenesis. Therefore, we compared regions of putative SOX9 DNA binding between E12.5 heart valves and E12.5 limb buds. We identified context-dependent and context-independent SOX9-interacting regions throughout the genome. Analysis of context-independent SOX9 binding suggests an extensive role for SOX9 across tissues in regulating proliferation-associated genes including key components of the AP-1 complex. Integrative analysis of tissue-specific SOX9-interacting regions and gene expression profiles on Sox9-deficient heart valves demonstrated that SOX9 controls the expression of several transcription factors with previously identified roles in heart valve development, including Twist1, Sox4, Mecom and Pitx2. Together, our data identify SOX9-coordinated transcriptional hierarchies that control cell proliferation and differentiation during valve formation.
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada V5Z 1L3 Program in Cell and Developmental Biology, University of British Columbia, Vancouver, Canada V6T 1Z4.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Garside
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada V5Z 1L3.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cullum
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada V5Z 1L3.
authors.forename: Olivia
authors.initials: O
authors.lastname: Alder
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada V5Z 1L3.
authors.forename: Daphne Y
authors.initials: DY
authors.lastname: Lu
authors.affiliation: Biomedical Research Centre, University of British Columbia, Vancouver, Canada V6T 1Z4.
authors.forename: Ryan
authors.initials: R
authors.lastname: Vander Werff
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada V5Z 1L3.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Bilenky
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada V5Z 1L3.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada V5Z 1L3 Department of Medical Genetics, University of British Columbia, Vancouver, Canada V6T 1Z4 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada V5A 1S6.
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada V5Z 1L3 Department of Medical Genetics, University of British Columbia, Vancouver, Canada V6T 1Z4.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Program in Cell and Developmental Biology, University of British Columbia, Vancouver, Canada V6T 1Z4 Biomedical Research Centre, University of British Columbia, Vancouver, Canada V6T 1Z4 Department of Medical Genetics, University of British Columbia, Vancouver, Canada V6T 1Z4.
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada V5Z 1L3 Program in Cell and Developmental Biology, University of British Columbia, Vancouver, Canada V6T 1Z4 Department of Medical Genetics, University of British Columbia, Vancouver, Canada V6T 1Z4 hoodless@bccrc.ca.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hoodless
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D005121:Extremities / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006351:Heart Valves / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; D004247:DNA
keywords: ChIP-Seq; Embryogenesis; Genome; Heart valves; Limb; Mouse; Proliferation; RNA-Seq; SOX9; Transcription factor; Transcriptional networks