title: Tissue-specific epigenetics in gene neighborhoods: myogenic transcription factor genes.
abstract: Myogenic regulatory factor (MRF) genes, MYOD1, MYOG, MYF6 and MYF5, are critical for the skeletal muscle lineage. Here, we used various epigenome profiles from human myoblasts (Mb), myotubes (Mt), muscle and diverse non-muscle samples to elucidate the involvement of multigene neighborhoods in the regulation of MRF genes. We found more far-distal enhancer chromatin associated with MRF genes in Mb and Mt than previously reported from studies in mice. For the MYF5/MYF6 gene-pair, regions of Mb-associated enhancer chromatin were located throughout the adjacent 236-kb PTPRQ gene even though Mb expressed negligible amounts of PTPRQ mRNA. Some enhancer chromatin regions inside PTPRQ in Mb were also seen in PTPRQ mRNA-expressing non-myogenic cells. This suggests dual-purpose PTPRQ enhancers that upregulate expression of PTPRQ in non-myogenic cells and MYF5/MYF6 in myogenic cells. In contrast, the myogenic enhancer chromatin regions distal to MYOD1 were intergenic and up to 19 kb long. Two of them contain small, known MYOD1 enhancers, and one displayed an unusually high level of 5-hydroxymethylcytosine in a quantitative DNA hydroxymethylation assay. Unexpectedly, three regions of MYOD1-distal enhancer chromatin in Mb and Mt overlapped enhancer chromatin in umbilical vein endothelial cells, which might upregulate a distant gene (PIK3C2A). Lastly, genes surrounding MYOG were preferentially transcribed in Mt, like MYOG itself, and exhibited nearby myogenic enhancer chromatin. These neighboring chromatin regions may be enhancers acting in concert to regulate myogenic expression of multiple adjacent genes. Our findings reveal the very different and complex organization of gene neighborhoods containing closely related transcription factor genes.
authors.affiliation: Program in Human Genetics, Tulane Cancer Center, and Center for Bioinformatics and Genomics, Tulane Health Sciences Center, New Orleans, LA 70122, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Chandra
authors.affiliation: New England Biolabs, Ipswich, MA 01938, USA.
authors.forename: Jolyon
authors.initials: J
authors.lastname: Terragni
authors.affiliation: New England Biolabs, Ipswich, MA 01938, USA.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: New England Biolabs, Ipswich, MA 01938, USA.
authors.forename: Sriharsa
authors.initials: S
authors.lastname: Pradhan
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98109, USA, and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Haushka
authors.affiliation: Department of Microbiology, Immunology and Parasitology, LSU Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Johnston
authors.affiliation: Tulane Cancer Center and Department of Mathematics, Tulane Health Sciences Center and Tulane University, New Orleans, LA 70122, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Baribault
authors.affiliation: Tulane Cancer Center and Department of Mathematics, Tulane Health Sciences Center and Tulane University, New Orleans, LA 70122, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lacey
authors.affiliation: Program in Human Genetics, Tulane Cancer Center, and Center for Bioinformatics and Genomics, Tulane Health Sciences Center, New Orleans, LA 70122, USA, ehrlich@tulane.edu.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ehrlich
mesh_terms: D000818:Animals; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases; D044127:Epigenesis, Genetic / Q000502:physiology*; D006801:Humans; D051379:Mice; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis* / Q000235:genetics; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018006:Myogenic Regulatory Factors; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C516917:PTPRQ protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3