title: Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation.
abstract: SET domain-containing proteins play a vital role in regulating gene expression during development through modifications in chromatin structure. Here we show that SET domain-containing 5 (Setd5) is divergently transcribed with Gt(ROSA26)Sor, is necessary for mammalian development, and interacts with the PAF1 co-transcriptional complex and other proteins. Setd5-deficient mouse embryos exhibit severe defects in neural tube formation, somitogenesis and cardiac development, have aberrant vasculogenesis in embryos, yolk sacs and placentas, and die between embryonic day 10.5 and 11.5. Setd5-deficient embryonic stem cells have impaired cellular proliferation, increased apoptosis, defective cell cycle progression, a diminished ability to differentiate into cardiomyocytes and greatly perturbed gene expression. SETD5 co-immunoprecipitates with multiple components of the PAF1 and histone deacetylase-containing NCoR complexes and is not solely required for major histone lysine methylation marks. In the absence of Setd5, histone acetylation is increased at transcription start sites and near downstream regions. These findings suggest that SETD5 functions in a manner similar to yeast Set3p and Drosophila UpSET, and that it is essential for regulating histone acetylation during gene transcription.
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.|Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Anna B
authors.identifier: 0000-0002-9513-2262
authors.initials: AB
authors.lastname: Osipovich
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Gangula
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Pedro G
authors.initials: PG
authors.lastname: Vianna
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA mark.magnuson@vanderbilt.edu.|Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Mark A
authors.identifier: 0000-0002-8824-6499
authors.initials: MA
authors.lastname: Magnuson
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology; D054259:Neural Tube / Q000254:growth & development; D011401:Promoter Regions, Genetic / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D006657:Histones; C547921:RNA polymerase II associated factor 1, mouse; D022661:RNA, Untranslated; D008780:Methyltransferases; C000621877:SETD5 protein, mouse
keywords: Embryogenesis; Histone acetylation; PAF1; Setd5; Transcription