Role of histone deacetylases in gene expression and RNA splicing

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dc.contributor.authorKhan, Dilshad Hussain
dc.contributor.examiningcommitteeMcManus, Kirk J (Biochemistry & Medical Genetics) Leygue, Etienne (Biochemistry & Medical Genetics) Kirshenbaum, Lorrie A (Physiology) Georgel, Philippe (Marshall University)en_US
dc.contributor.supervisorDavie, Jim R (Biochemistry & Medical Genetics)en_US
dc.date.accessioned2013-09-11T14:37:33Z
dc.date.available2013-09-11T14:37:33Z
dc.date.issued2012-10-15en_US
dc.date.issued2012-04-28en_US
dc.date.issued2012-03-12en_US
dc.date.issued2012-12-31en_US
dc.date.issued2013-03-29en_US
dc.date.issued2013-04-23en_US
dc.degree.disciplineBiochemistry and Medical Geneticsen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractHistone deacetylases (HDAC) 1 and 2 play crucial role in chromatin remodeling and gene expression regimes, as part of multiprotein corepressor complexes. Protein kinase CK2-driven phosphorylation of HDAC1 and 2 regulates their catalytic activities and is required to form the corepressor complexes. Phosphorylation-mediated differential distributions of HDAC1 and 2 complexes in regulatory and coding regions of transcribed genes catalyze the dynamic protein acetylation of histones and other proteins, thereby influence gene expression. During mitosis, highly phosphorylated HDAC1 and 2 heterodimers dissociate and displace from mitotic chromosomes. Our goal was to identify the kinase involved in mitotic phosphorylation of HDAC1 and 2. We postulated that CK2-mediated increased phosphorylation of HDAC1 and 2 leads to dissociation of the heterodimers, and, the mitotic chromosomal exclusions of HDAC1 and 2 are largely due to the displacement of HDAC-associated proteins and transcription factors, which recruit HDACs, from chromosomes during mitosis. We further explored the role of un- or monomodified HDAC1 and 2 complexes in immediate-early genes (IEGs), FOSL1 (FOS-like antigen-1) and MCL1 (Myeloid cell leukemia-1), regulation. Dynamic histone acetylation is an important regulator of these genes that are overexpressed in a number of diseases and cancers. We hypothesized that transcription dependent recruitment of HDAC1 and 2 complexes over the gene body regions plays a regulatory role in transcription and splicing regulation of these genes. We present evidence that CK2-catalyzed increased phosphorylation of HDAC1 and 2 regulates the formation of distinct corepressor complexes containing either HDAC1 or HDAC2 homodimers during mitosis, which might target cellular factors. Furthermore, the exclusion of HDAC-recruiting proteins is the major factor for their displacement from mitotic chromosomes. We further demonstrated that un- or monophosphorylated HDAC1 and 2 are associated with gene body of FOSL1 in a transcription dependent manner. However, HDAC inhibitors prevented FOSL1 activation independently of the nucleosome response pathway, which is required for IEG induction. Interestingly, our mass spectrometry results revealed that HDAC1 and 2 interact with a number of splicing proteins, in particular, with serine/arginine-rich splicing factor 1 (SRSF1). HDAC1 and 2 are co-occupied with SRSF1 over gene body regions of FOSL1 and MCL1, regardless of underlying splicing mechanisms. Using siRNA-mediated knockdown approaches and HDAC inhibitors, we demonstrated that alternative splicing of MCL1 is regulated by RNA-directed localized changes in the histone acetylation levels at the alternative exon. The change in histone acetylation levels correlates with the increased transcription elongation and results in change in MCL1 splicing by exon skipping mechanism. Taken together, our results contribute to further understanding of how the multi-faceted HDAC1 and 2 complexes can be regulated and function in various processes, including, but not limited to, transcription regulation and alternative splicing. This can be an exciting area of future research for therapeutic interventions.en_US
dc.description.noteOctober 2013en_US
dc.identifier.citationDelcuve GP, Khan DH, Davie JR. Targeting class I histone deacetylases in cancer therapy. Expert Opin Ther Targets. 17(1):29-41, 2013.en_US
dc.identifier.citationKhan DH, Jahan S, Davie JR. Pre-mRNA splicing: role of epigenetics and implications in disease. Adv Biol Regul. 52(3):377-88, 2012en_US
dc.identifier.citationDelcuve GP, Khan DH, Davie JR. Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors. Clin Epigenetics. 4(1):5, 2012en_US
dc.identifier.citationDynamic distribution of HDAC1 and HDAC2 during mitosis: association with F-actin.J. Cell. Physiol. 228: 1525–1535, 2013en_US
dc.identifier.citationHDAC inhibitors prevent the activation of immediate-early gene FOSL1, but do not alter the nucleosome response. FEBS Lett. 587(10):1510-1517, 2013en_US
dc.identifier.citationProtein kinase CK2 regulates the dimerization of histone deacetylase (HDAC) 1 and HDAC2 during mitosis.J Biol Chem. 288(23):16518-16528, 2013en_US
dc.identifier.urihttp://hdl.handle.net/1993/22163
dc.language.isoengen_US
dc.publisherInforma UK Limiteden_US
dc.publisherElsevier Ltden_US
dc.publisherBioMed Central Ltden_US
dc.publisherWiley Periodicals, Incen_US
dc.publisherElsevier B.Ven_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.rightsopen accessen_US
dc.subjectHistone deacetylasesen_US
dc.subjectgene expressionen_US
dc.subjectsplicingen_US
dc.subjectchromatin immunoprecipitationen_US
dc.subjectimmediate-early genesen_US
dc.subjectprotein kinase CK2en_US
dc.subjectHDAC inhibitorsen_US
dc.subjectmitosisen_US
dc.titleRole of histone deacetylases in gene expression and RNA splicingen_US
dc.typedoctoral thesisen_US
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