title: Mammalian X upregulation is associated with enhanced transcription initiation, RNA half-life, and MOF-mediated H4K16 acetylation.
abstract: X upregulation in mammals increases levels of expressed X-linked transcripts to compensate for autosomal biallelic expression. Here, we present molecular mechanisms that enhance X expression at transcriptional and posttranscriptional levels. Active mouse X-linked promoters are enriched in the initiation form of RNA polymerase II (PolII-S5p) and in specific histone marks, including histone H4 acetylated at lysine 16 (H4K16ac) and histone variant H2AZ. The H4K16 acetyltransferase males absent on the first (MOF), known to mediate the Drosophila X upregulation, is also enriched on the mammalian X. Depletion of MOF or male-specific lethal 1 (MSL1) in mouse ES cells causes a specific decrease in PolII-S5p and in expression of a subset of X-linked genes. Analyses of RNA half-life data sets show increased stability of mammalian X-linked transcripts. Both ancestral X-linked genes, defined as those conserved on chicken autosomes, and newly acquired X-linked genes are upregulated by similar mechanisms but to a different extent, suggesting that subsets of genes are distinctly regulated depending on their evolutionary history.
authors.affiliation: Department of Pathology, School of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Xinxian
authors.initials: X
authors.lastname: Deng
authors.forename: Joel B
authors.initials: JB
authors.lastname: Berletch
authors.forename: Wenxiu
authors.initials: W
authors.lastname: Ma
authors.forename: Di Kim
authors.initials: DK
authors.lastname: Nguyen
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Hiatt
authors.forename: William S
authors.initials: WS
authors.lastname: Noble
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Christine M
authors.initials: CM
authors.lastname: Disteche
mesh_terms: D000107:Acetylation; D000818:Animals; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D019143:Evolution, Molecular; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D050172:Genes, X-Linked; D006207:Half-Life; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008322:Mammals / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014960:X Chromosome / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D012333:RNA, Messenger; D051548:Histone Acetyltransferases; C000622683:Kat8 protein, mouse; D012319:RNA Polymerase II