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Zhao, Lijuan

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Zhao

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Lijuan

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Zhao, Lijuan

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2016 - 201912020 - 20211

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Author's Publications: search.filters.isAuthorOfPublication.8ac197a7-5535-4823-9c7a-5408cdfe71fa

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    Orientation-specific RAG activity in chromosomal loop domains contributes to Tcrd V(D)J recombination during T cell development
    (The Rockefeller University Press, 2016) Zhao, Lijuan; Frock, Richard Lee; Du, Zhou; Hu, Jiazhi; Chen, Liang; Krangel, Michael S.; Alt, Frederick
    T cell antigen receptor δ (Tcrd) variable region exons are assembled by RAG-initiated V(D)J recombination events in developing γδ thymocytes. Here, we use linear amplification–mediated high-throughput genome-wide translocation sequencing (LAM-HTGTS) to map hundreds of thousands of RAG-initiated Tcrd D segment (Trdd1 and Trdd2) rearrangements in CD4−CD8− double-negative thymocyte progenitors differentiated in vitro from bone marrow–derived hematopoietic stem cells. We find that Trdd2 joins directly to Trdv, Trdd1, and Trdj segments, whereas Trdd1 joining is ordered with joining to Trdd2, a prerequisite for further rearrangement. We also find frequent, previously unappreciated, Trdd1 and Trdd2 rearrangements that inactivate Tcrd, including sequential rearrangements from V(D)J recombination signal sequence fusions. Moreover, we find dozens of RAG off-target sequences that are generated via RAG tracking both upstream and downstream from the Trdd2 recombination center across the Tcrd loop domain that is bounded by the upstream INT1-2 and downstream TEA elements. Disruption of the upstream INT1-2 boundary of this loop domain allows spreading of RAG on- and off-target activity to the proximal Trdv domain and, correspondingly, shifts the Tcrd V(D)J recombination landscape by leading to predominant V(D)J joining to a proximal Trdv3 pseudogene that lies just upstream of the normal boundary.
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    Loop Extrusion Mediates Physiological IgH Locus Contraction For RAG Scanning
    (Springer Science and Business Media LLC, 2021-01-13) Dai, Hai-Qiang; Hu, Hongli; Lou, Jiangman; Ye, Adam Yongxin; Zhang, Xuefei; Zhang, Yiwen; Zhao, Lijuan; Yoon, Hye; Ba, Zhaoqing; Chapdelaine-Williams, Aimee M.; Kyritsis, Nia; Chen, Huan; Johnson, Kerstin; Lin, Sherry; Conte, Andrea; Casellas, Rafael; Lee, Cheng-Sheng; Alt, Frederick
    RAG endonuclease initiates IgH V(D)J recombination in pro-B cells by binding a JH-recombination signal sequence (RSS) within a recombination center (RC) and then linearly scanning upstream chromatin, presented by cohesin-mediated loop extrusion, for convergent D-RSSs1,2. Utilization of convergently-oriented RSSs and cryptic RSSs is intrinsic to long-range RAG scanning3. RAG scanning from the DJH-RC-RSS to upstream convergent VH-RSSs is impeded by D-proximal CTCF-binding elements (CBEs)2-5. Primary pro-B cells undergo a mechanistically-undefined VH locus contraction proposed to provide distal VHs access to the DJH-RC6-9. Here, we report that a 2.4 mega-base VH locus inversion in primary pro-B cells abrogates rearrangement of both VH-RSSs and normally convergent cryptic RSSs, even though locus contraction still occurs. In addition, this inversion activated both utilization of cryptic VH-locus RSSs normally in opposite orientation and RAG scanning beyond the VH locus through multiple convergent-CBE domains to the telomere. Together, these findings imply that broad deregulation of CBE impediments in primary pro-B cells promotes loop extrusion-mediated RAG VH locus-scanning. We further found that expression of Wapl10, a cohesin-unloading factor, is low in primary pro-B cells versus v-Abl-transformed pro-B lines that lack contraction and RAG-scanning of the VH locus. Correspondingly, Wapl depletion in v-Abl-tranformed lines activated both processes, further implicating loop extrusion in the locus contraction mechanism.