A dynamical model of TCRβgene recombination: Coupling the initiation of Dβ-Jβrearrangement to TCRβallelic exclusion

Abstract

One paradigm of random monoallelic gene expression is that of T-cell receptor (TCR) allelic exclusion in T lymphocytes. However, the dynamics that sustain asymmetric choice in TCR dual allele usage and the production of TCR monoallelic expressing T-cells remain poorly understood. Here, we develop a computational model to explore a scheme of TCR allelic exclusion based on the stochastic initiation of DNA rearrangement [V(D)J recombination] at homologous alleles in T-cell progenitors, and thus account for the genotypic profiles typically associated with allelic exclusion in differentiated T-cells. Disturbances in these dynamics at the level of an individual allele have limited consequences on these profiles, a robust feature of the system that is underscored by our simulations. Our study predicts a biological system in which locus-specific, prime epigenetic allelic activation effects set the stage to both optimize the production of TCR allelically excluded T-cells and curtail the emergence of their allelically included counterparts.

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“…In the studies that involved insertion of a Db-Jb recombination substrate into the endogenous Vb14 gene segment, accessibility for recombination upon the inserted reporter remained dependent on epigenetically modulated chromatin conformation (64). The significance of this euchromatin-to-heterochromatin transition in health and disease is the subject of intense research aimed at identification of the combination of histone marks (e.g., H3K4ac, H3K4me) that possibly produce restriction at V(D)J rearranging loci (62,63,65). It is possible that active epigenetic marks are established through the recombining gene segments and associated RSs before AR V(D)J assembly by interaction with either sense or antisense GT (66,67).…”