title: A structural hierarchy mediated by multiple nuclear factors establishes IgH locus conformation.
abstract: Conformation of antigen receptor gene loci spatially juxtaposes rearranging gene segments in the appropriate cell lineage and developmental stage. We describe a three-step pathway that establishes the structure of the 2.8-Mb immunoglobulin heavy chain gene (IgH) locus in pro-B cells. Each step uses a different transcription factor and leads to increasing levels of structural organization. CTCF mediates one level of compaction that folds the locus into several 250- to 400-kb subdomains, and Pax5 further compacts the 2-Mb region that encodes variable (VH) gene segments. The 5' and 3' domains are brought together by the transcription factor YY1 to establish the configuration within which gene recombination initiates. Such stepwise mechanisms may apply more generally to establish regulatory fine structure within megabase-sized topologically associated domains.
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland 21224, USA;
authors: Tatiana
authors: T
authors: Gerasimova
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland 21224, USA;
authors: Changying
authors: C
authors: Guo
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland 21224, USA;
authors: Amalendu
authors: A
authors: Ghosh
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland 21224, USA;
authors: Xiang
authors: X
authors: Qiu
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland 21224, USA;
authors: Lindsey
authors: L
authors: Montefiori
authors: The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Jiyoti
authors: J
authors: Verma-Gaur
authors: The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Nancy M
authors: NM
authors: Choi
authors: The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Ann J
authors: AJ
authors: Feeney
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland 21224, USA;
authors: Ranjan
authors: R
authors: Sen
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D002478:Cells, Cultured; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry* / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D008810:Mice, Inbred C57BL; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D055291:Salivary alpha-Amylases / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619698:Ctcf protein, mouse; D007143:Immunoglobulin Heavy Chains; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D012097:Repressor Proteins; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse; C524799:Amy1 protein, mouse; D055291:Salivary alpha-Amylases
keywords: architectural proteins; chromosome conformation; looping