Extremely Long-Range Chromatin.pdf (2.1 MB)
Extremely Long-Range Chromatin Loops Link Topological Domains to Facilitate a Diverse Antibody Repertoire.
journal contributionposted on 2016-06-21, 00:00 authored by L Montefiori, R Wuerffel, D Roqueiro, B Lajoie, C Guo, T Gerasimova, S De, W Wood, KG Becker, J Dekker, J Liang, R Sen, AL Kenter
Early B cell development is characterized by large-scale Igh locus contraction prior to V(D)J recombination to facilitate a highly diverse Ig repertoire. However, an understanding of the molecular architecture that mediates locus contraction remains unclear. We have combined high-resolution chromosome conformation capture (3C) techniques with 3D DNA FISH to identify three conserved topological subdomains. Each of these topological folds encompasses a major VH gene family that become juxtaposed in pro-B cells via megabase-scale chromatin looping. The transcription factor Pax5 organizes the subdomain that spans the VHJ558 gene family. In its absence, the J558 VH genes fail to associate with the proximal VH genes, thereby providing a plausible explanation for reduced VHJ558 gene rearrangements in Pax5-deficient pro-B cells. We propose that Igh locus contraction is the cumulative effect of several independently controlled chromatin subdomains that provide the structural infrastructure to coordinate optimal antigen receptor assembly.
This work was supported by the National Institutes of Health (RO1AI052400, R21AI117687 to A.K., HG003143 and HG00459 to J.D., GM079804 to J.L.), National Science Foundation (DBI 1062328 and MCB-1415589 to J.L.), the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (to A.K. and J.L.), the W.M. Keck Foundation (to J.D.), and Intramural Research Program of the National Institute on Aging (Baltimore, MD) (to R.S.)
Publisher StatementThis is a copy of an article published in Cell Reports © 2016 Elsevier (Cell Press) Publications. © 2016 The Authors. http://dx.doi.org/10.1016/j.celrep.2015.12.083
PublisherElsevier (Cell Press)