| First Author | Ba Z | Year | 2020 |
| Journal | Nature | Volume | 586 |
| Issue | 7828 | Pages | 305-310 |
| PubMed ID | 32717742 | Mgi Jnum | J:297408 |
| Mgi Id | MGI:6472591 | Doi | 10.1038/s41586-020-2578-0 |
| Citation | Ba Z, et al. (2020) CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning. Nature 586(7828):305-310 |
| abstractText | The RAG endonuclease initiates Igh locus V(D)J recombination in progenitor (pro)-B cells(1). Upon binding a recombination centre-based JH, RAG scans upstream chromatin via loop extrusion, potentially mediated by cohesin, to locate Ds and assemble a DJH-based recombination centre(2). CTCF looping factor-bound elements (CBEs) within IGCR1 upstream of Ds impede RAG scanning(3-5); however, their inactivation allows scanning to proximal VHs, where additional CBEs activate rearrangement and impede scanning any further upstream(5). Distal VH utilization is thought to involve diffusional access to the recombination centre following large-scale Igh locus contraction(6-8). Here we test the potential of linear RAG scanning to mediate distal VH usage in G1-arrested v-Abl pro-B cell lines(9), which undergo robust D-to-JH but little VH-to-DJH rearrangements, presumably owing to lack of locus contraction(2,5). Through an auxin-inducible approach(10), we degraded the cohesin component RAD21(10-12) or CTCF(12,13) in these G1-arrested lines. Degradation of RAD21 eliminated all V(D)J recombination and interactions associated with RAG scanning, except for reecombination centre-located DQ52-to-JH joining, in which synapsis occurs by diffusion(2). Remarkably, while degradation of CTCF suppressed most CBE-based chromatin interactions, it promoted robust recombination centre interactions with, and robust VH-to-DJH joining of, distal VHs, with patterns similar to those of 'locus-contracted' primary pro-B cells. Thus, downmodulation of CTCF-bound scanning-impediment activity promotes cohesin-driven RAG scanning across the 2.7-Mb Igh locus. |
