title: Transcription factor Ikaros represses protein phosphatase 2A (PP2A) expression through an intronic binding site.
abstract: Protein phosphatase 2A (PP2A) is a highly conserved and ubiquitous serine/threonine phosphatase. We have shown previously that PP2A expression is increased in T cells of systemic lupus erythematosus patients and that this increased expression and activity of PP2A plays a central role in the molecular pathogenesis of systemic lupus erythematosus. Although the control of PP2A expression has been the focus of many studies, many aspects of its regulation still remain poorly understood. In this study, we describe a novel mechanism of PP2A regulation. We propose that the transcription factor Ikaros binds to a variant site in the first intron of PP2A and modulates its expression. Exogenous expression of Ikaros leads to reduced levels of PP2Ac message as well as protein. Conversely, siRNA-enabled silencing of Ikaros enhances the expression of PP2A, suggesting that Ikaros acts as a suppressor of PP2A expression. A ChIP analysis further proved that Ikaros is recruited to this site in T cells. We also attempted to delineate the mechanism of Ikaros-mediated PP2Ac gene suppression. We show that Ikaros-mediated suppression of PP2A expression is at least partially dependent on the recruitment of the histone deacetylase HDAC1 to this intronic site. We conclude that the transcription factor Ikaros can regulate the expression of PP2A by binding to a site in the first intron and modulating chromatin modifications at this site via recruitment of HDAC1.
authors.affiliation: From the Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115 and knagpal@bidmc.harvard.edu.
authors.forename: Kamalpreet
authors.initials: K
authors.lastname: Nagpal
authors.affiliation: From the Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115 and.
authors.forename: Katsue Sunahori
authors.initials: KS
authors.lastname: Watanabe
authors.affiliation: the Division of Rheumatology, University of California Los Angeles, Los Angeles, California 90095.
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.affiliation: From the Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115 and gtsokos@bidmc.harvard.edu.
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D007438:Introns; D011401:Promoter Regions, Genetic / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics*; D021381:Protein Transport; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; D051740:Ikaros Transcription Factor; D054648:Protein Phosphatase 2; D056284:Histone Deacetylase 1
keywords: Chromatin Modification; Gene Regulation; Protein Phosphatase; T Cell; Transcription Repressor