title: Dual Mechanism ofRagGene Repression by c-Myb during Pre-B Cell Proliferation.
abstract: Developing B lymphocytes undergo clonal expansion following successful immunoglobulin heavy chain gene rearrangement. During this proliferative burst, expression of theRaggenes is transiently repressed to prevent the generation of double-stranded DNA (dsDNA) breaks in cycling large pre-B cells. TheRaggenes are then reexpressed in small, resting pre-B cells for immunoglobulin light chain gene rearrangement. We previously identified c-Myb as a repressor ofRagtranscription during clonal expansion using Abelson murine leukemia virus-transformed B cells. Nevertheless, the molecular mechanisms by which c-Myb achieved precise spatiotemporal repression ofRagexpression remained obscure. Here, we identify two mechanisms by which c-Myb repressesRagtranscription. First, c-Myb negatively regulates the expression of theRagactivator Foxo1, an activity dependent on M303 in c-Myb's transactivation domain, and likely the recruitment of corepressors to theFoxo1locus by c-Myb. Second, c-Myb repressesRagtranscription directly by occupying the Eragenhancer and antagonizing Foxo1 binding to a consensus forkhead site in thiscis-regulatory element that we show is crucial forRagexpression in Abelson pre-B cell lines. This work provides important mechanistic insight into how spatiotemporal expression of theRaggenes is tightly controlled during B lymphocyte development to prevent mistimed dsDNA breaks and their deleterious consequences.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Timblin
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Liangqi
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.|Office of the President, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tjian
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA markschl@umich.edu.|Office of the President, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Mark S
authors.identifier: http://orcid.org/0000-0003-2271-0196
authors.initials: MS
authors.lastname: Schlissel
mesh_terms: D000818:Animals; D001665:Binding Sites; D064113:CRISPR-Cas Systems / Q000235:genetics; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D018398:Homeodomain Proteins; D020598:Proto-Oncogene Proteins c-myb; C499308:Rag2 protein, mouse; D012097:Repressor Proteins; C064658:RAG-1 protein
keywords: B cell development; V(D)J recombination; c-Myb; chromatin remodeling; transcriptional regulation