title: Hu proteins regulate alternative splicing by inducing localized histone hyperacetylation in an RNA-dependent manner.
abstract: Recent studies have provided strong evidence for a regulatory link among chromatin structure, histone modification, and splicing regulation. However, it is largely unknown how local histone modification patterns surrounding alternative exons are connected to differential alternative splicing outcomes. Here we show that splicing regulator Hu proteins can induce local histone hyperacetylation by association with their target sequences on the pre-mRNA surrounding alternative exons of two different genes. In both primary and mouse embryonic stem cell-derived neurons, histone hyperacetylation leads to an increased local transcriptional elongation rate and decreased inclusion of these exons. Furthermore, we demonstrate that Hu proteins interact with histone deacetylase 2 and inhibit its deacetylation activity. We propose that splicing regulators may actively modulate chromatin structure when recruited to their target RNA sequences cotranscriptionally. This "reaching back" interaction with chromatin provides a means to ensure accurate and efficient regulation of alternative splicing.
authors.affiliation: Department of Genetics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Zhou
authors.forename: Melissa N
authors.initials: MN
authors.lastname: Hinman
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Barron
authors.forename: Cuiyu
authors.initials: C
authors.lastname: Geng
authors.forename: Guangjin
authors.initials: G
authors.lastname: Zhou
authors.forename: Guangbin
authors.initials: G
authors.lastname: Luo
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Siegel
authors.forename: Hua
authors.initials: H
authors.lastname: Lou
mesh_terms: D000107:Acetylation; D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D051959:ELAV Proteins / Q000378:metabolism*; D005091:Exons / Q000502:physiology; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012322:RNA Precursors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D002843:Chromatin; D051959:ELAV Proteins; D006657:Histones; D012322:RNA Precursors; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2