Dynamics of intra-TAD and inter-TAD interactions controlled by a bi-directionally transcribed DNA element determines tissue specific antibody gene diversification

The function in antibody gene diversification mechanisms of the many topological associated domains (TADs) flanking the IgH locus in the mammalian genome is incompletely understood. In this study, we have identified an evolutionarily conserved TAD, known as TADlncCSRIgA, that coordinates antibody gene diversification mechanisms of somatic hypermutation and class switch recombination specifically in IgA-expressing Peyer's patch B cells in the gut. Molecular dissection of the TADlncCSRIgA demonstrates that a bidirectional noncoding RNA expressing element lncRNA-CSRIgA is crucial in orchestrating physical interaction of a critical CTCF site (CTCFlncCSR) to two genomic loci inside the TADlncCSRIgA and with the distal TADIgH. Ablation of lncCSR-IgA leads to dis-balance in both intra-TADlncCSRIgA and inter-TAD interactions (intra-TADlncCSRIgA with TADIgH), potentially due to lack of control of FACT complex recruitment at the critical CTCFlncCSR. Genome wide analysis identified many other similar intra-TAD and inter-TAD interactions that are potentially controlled by bidirectional transcription flanking pivotal CTCF sites in the mouse genome, thus bringing forth a novel mechanism of genome organization regulation during cellular development and homeostasis.