title: Unifying model for molecular determinants of the preselection Vβ repertoire.
abstract: The primary antigen receptor repertoire is sculpted by the process of V(D)J recombination, which must strike a balance between diversification and favoring gene segments with specialized functions. The precise determinants of how often gene segments are chosen to complete variable region coding exons remain elusive. We quantified Vβ use in the preselection Tcrb repertoire and report relative contributions of 13 distinct features that may shape their recombination efficiencies, including transcription, chromatin environment, spatial proximity to their DβJβ targets, and predicted quality of recombination signal sequences (RSSs). We show that, in contrast to functional Vβ gene segments, all pseudo-Vβ segments are sequestered in transcriptionally silent chromatin, which effectively suppresses wasteful recombination. Importantly, computational analyses provide a unifying model, revealing a minimum set of five parameters that are predictive of Vβ use, dominated by chromatin modifications associated with transcription, but largely independent of precise spatial proximity to DβJβ clusters. This learned model-building strategy may be useful in predicting the relative contributions of epigenetic, spatial, and RSS features in shaping preselection V repertoires at other antigen receptor loci. Ultimately, such models may also predict how designed or naturally occurring alterations of these loci perturb the preselection use of variable gene segments.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine in St Louis, St Louis, MO 63110, USA.
authors.forename: Suhasni
authors.initials: S
authors.lastname: Gopalakrishnan
authors.forename: Kinjal
authors.initials: K
authors.lastname: Majumder
authors.forename: Alexander
authors.initials: A
authors.lastname: Predeus
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.forename: Olivia I
authors.initials: OI
authors.lastname: Koues
authors.forename: Jiyoti
authors.initials: J
authors.lastname: Verma-Gaur
authors.forename: Salvatore
authors.initials: S
authors.lastname: Loguercio
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Su
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Feeney
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Oltz
mesh_terms: D000818:Animals; D002843:Chromatin / Q000276:immunology; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology / Q000379:methods; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology*; D019674:Genes, T-Cell Receptor beta / Q000235:genetics* / Q000276:immunology*; D059014:High-Throughput Nucleotide Sequencing; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D012044:Regression Analysis; D060152:V(D)J Recombination / Q000235:genetics / Q000276:immunology*
chemical_list: D002843:Chromatin; D017931:DNA Primers; D007135:Immunoglobulin Variable Region; D008156:Luciferases
keywords: T-cell receptor; gene regulation; lymphocytes
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