title: SOX9 chromatin folding domains correlate with its real and putative distant cis-regulatory elements.
abstract: Evolutionary conserved transcription factor SOX9, encoded by the dosage sensitive SOX9 gene on chromosome 17q24.3, plays an important role in development of multiple organs, including bones and testes. Heterozygous point mutations and genomic copy-number variant (CNV) deletions involving SOX9 have been reported in patients with campomelic dysplasia (CD), a skeletal malformation syndrome often associated with male-to-female sex reversal. Balanced and unbalanced structural genomic variants with breakpoints mapping up to 1.3 Mb up- and downstream to SOX9 have been described in patients with milder phenotypes, including acampomelic campomelic dysplasia, sex reversal, and Pierre Robin sequence. Based on the localization of breakpoints of genomic rearrangements causing different phenotypes, 5 genomic intervals mapping upstream to SOX9 have been defined. We have analyzed the publically available database of high-throughput chromosome conformation capture (Hi-C) in multiple cell lines in the genomic regions flanking SOX9. Consistent with the literature data, chromatin domain boundaries in the SOX9 locus exhibit conservation across species and remain largely constant across multiple cell types. Interestingly, we have found that chromatin folding domains in the SOX9 locus associate with the genomic intervals harboring real and putative regulatory elements of SOX9, implicating that variation in intra-domain interactions may be critical for dynamic regulation of SOX9 expression in a cell type-specific fashion. We propose that tissue-specific enhancers for other transcription factor genes may similarly utilize chromatin folding sub-domains in gene regulation.
authors.affiliation: a Department of Medical Genetics , Institute of Mother and Child , Warsaw , Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Smyk
authors.affiliation: b Genomic Medicine Department , MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Kadir Caner
authors.initials: KC
authors.lastname: Akdemir
authors.affiliation: c Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D055036:Campomelic Dysplasia / Q000235:genetics; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002877:Chromosomes, Human / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D012045:Regulatory Sequences, Nucleic Acid; D055758:SOX9 Transcription Factor / Q000235:genetics*
chemical_list: D002843:Chromatin; D055758:SOX9 Transcription Factor
keywords: chromatin looping; long distance gene regulation; non-coding variants; structural variants; tissue-specific enhancers