The HoxC4 homeodomain protein mediates activation of the immunoglobulin heavy chain 3' hs1,2 enhancer in human B cells. Relevance to class switch DNA recombination

The Journal of Biological Chemistry
Edmund C KimPaolo Casali

Abstract

The immunoglobulin heavy chain (IgH) 3' regulatory region modulates IgH locus transcription, upon induction by specific trans-acting factors, and plays a significant role in class switch DNA recombination (CSR) and, perhaps, somatic hypermutation (SHM). CSR and SHM are central to the maturation of the antibody response. In contrast to the single 5'-hs3a-hs1,2-hs3b-hs4-3 ' mouse IgH 3 ' regulatory region, the human IgH 3 ' regulatory region exists as a 5'-hs3-hs1,2-hs4-3' cluster duplicated 3 ' of Calpha1 and Calpha2. We show here that the human hs1,2 element is the strongest enhancer of transcription, as directed by a V(H)1 or the ECS-Igamma3 promoter, thereby suggesting a dominant role for hs1,2 over hs3 and hs4 in the overall activity of the 3 ' regulatory region. Within hs1,2, we identified three regions (1, 2, and 3) that are all necessary, but individually not sufficient, for enhancement of transcription. In region 2, a HoxC4 site and a HoxC4/embedded octamer (HoxC4/Oct) site are conserved across human, mouse, rat, and rabbit. These two sites recruit HoxC4 and Oct-1/Oct-2, which act synergistically with the Oca-B coactivator to effect the full hs1,2-enhancing activity. HoxC4, Oct-1/Oct-2, and Oca-B recruitment is negligibl...Continue Reading

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Citations

Jun 26, 2012·Nature Reviews. Immunology·Zhenming XuPaolo Casali
Aug 24, 2010·Nature Structural & Molecular Biology·Zhenming XuPaolo Casali
Jul 15, 2005·Annals of the New York Academy of Sciences·Zhenming XuPaolo Casali
Sep 18, 2015·Toxicological Sciences : an Official Journal of the Society of Toxicology·Richard L Salisbury, Courtney E W Sulentic
Feb 15, 2018·Acta Diabetologica·Rossella CianciDomenico Frezza
May 24, 2018·Human Molecular Genetics·Bethany CrawfordTherese M Murphy
Dec 17, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Vincenzo GiambraDomenico Frezza

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