title: The eleven-nineteen lysine-rich leukemia gene (ELL2) influences the histone H3 protein modifications accompanying the shift to secretory immunoglobulin heavy chain mRNA production.
abstract: In plasma cells, immunoglobulin heavy chain (IgH) secretory-specific mRNA is made in high abundance as a result of both increased promoter proximal poly(A) site choice and weak splice-site skipping. Ell2, the eleven-nineteen lysine rich leukemia gene, is a transcription elongation factor that is induced ∼6-fold in plasma cells and has been shown to drive secretory-specific mRNA production. Reducing ELL2 by siRNA, which reduced processing to the secretion-specific poly(A) site, also influenced the methylations of histone H3K4 and H3K79 on the IgH gene and impacted positive transcription factor b (pTEFb), Ser-2 carboxyl-terminal phosphorylation, and polyadenylation factor additions to RNA polymerase II. The multiple lineage leukemia gene (MLL) and Dot1L associations with the IgH gene were also impaired in the absence of ELL2. To investigate the link between histone modifications, transcription elongation, and alternative RNA processing in IgH mRNA production, we performed chromatin immunoprecipitation on cultured mouse B and plasma cells bearing the identical IgH γ2a gene. In the plasma cells, as compared with the B cells, the H3K4 and H3K79 methylations extended farther downstream, past the IgH enhancer to the end of the transcribed region. Thus the downstream H3K4 and H3K79 methylation of the IgH associated chromatin in plasma cells is associated with increased polyadenylation and exon skipping, resulting from the actions of ELL2 transcription elongation factor.
authors.affiliation: Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. milcarek@pitt.edu
authors.forename: Christine
authors.initials: C
authors.lastname: Milcarek
authors.forename: Michael
authors.initials: M
authors.lastname: Albring
authors.forename: Creityeka
authors.initials: C
authors.lastname: Langer
authors.forename: Kyung Soo
authors.initials: KS
authors.lastname: Park
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005091:Exons / Q000502:physiology; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007142:Immunoglobulin gamma-Chains / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008745:Methylation; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D026723:Polyadenylation / Q000502:physiology; D039104:RNA 3' Polyadenylation Signals / Q000502:physiology*; D012319:RNA Polymerase II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology*; D035602:Transcriptional Elongation Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D002843:Chromatin; C568074:ELL2 protein, mouse; D006657:Histones; D007142:Immunoglobulin gamma-Chains; D034741:RNA, Small Interfering; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D012319:RNA Polymerase II