Antigen receptor gene recombination requires stochastic, monoallelic choice of a single variable gene in each lymphocyte progenitor. However, how this occurs remains unknown. Herein, we report that prior to V to J gene recombination, Ig alleles reside within spatially different nuclear niches defined by elongating RNA Polymerase II (e-Pol II) and cyclin D3 complexes assembled on the nuclear matrix. Upon cell cycle exit, and cyclin D3 downregulation, only the V allele in the more constrained e-Pol II niche was transcribed. Chromatin modeling and single cell RNA-seq revealed that the nuclear niche favored V flanking CTCF sites, thus shaping the transcribed repertoire. Furthermore, multiple contiguous Vs oriented away from CTCF sites were preferentially transcribed. Cyclin D3 also repressed monoallelic protocadherin and olfactory genes. These studies of Ig reveal a general mechanism by which regulated, stochastic chromatin loop capture by fixed e-Pol II complexes generates diversity and couples cell cycle exit to monogenic choice. SOURCE: Mark Maienschein-Cline (mmaiensc@uic.edu) - Center for Research Informatics University of Illinois at Chicago

Pluto Bioinformatics

GSE84705: Stochastic capture of chromatin topological domains by nuclear matrix RNA polymerase II determines monogenic choice