rigrag: high-resolution mapping of genic targeting preferences during HIV-1 integration in vitro and in vivo.
rigrag: high-resolution mapping of genic targeting preferences during HIV-1 integration in vitro and in vivo.
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DOI：
10.1093/nar/gkab514
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发表时间：
2021-07-21
影响因子：
14.9
通讯作者：
Engelman AN
中科院分区：
文献类型：
--
作者：
Bedwell GJ;Jang S;Li W;Singh PK;Engelman AN
HIV-1整合有利于复发整合基因（RIG）的目标和基因前病毒可以赋予细胞在体内的生存。然而，初始RIG整合子之间的关系以及这些整合子如何随时间在患者中演变尚不清楚。为了解决这些缺点，我们建立了计算机随机整合的现象学模型，用于从10个体外数据集的170万个整合位点中识别3718个RIG以及2150个复发性避免基因。尽管RIG仅包含13%的人类基因，但它们在体外和患者来源的数据集中包含了70%的HIV-1基因整合。虽然先前报道与超级增强子相关，但RIGs更强烈地追踪斑点相关域。尽管整合酶辅因子LEDGF/p75的耗竭显著降低了体外复发性HIV-1整合，但LEDGF/p75主要占据染色质的非斑点相关区域，表明LEDGF/p75功能在HIV-1整合靶向中的先前未被认识到的动态方面。最后，我们从患者样本中仅鉴定出6个基因-BACH 2、STAT 5 B、MKL 1、MKL 2、IL 2 RB和MDC 1--它们显示出丰富的整合靶向频率，并含有可能有助于细胞存活的前病毒。因此，尽管已知HIV-1倾向于靶向癌症相关基因进行整合，但我们得出结论，基因前病毒在体内直接影响细胞增殖方面发挥的作用有限。
HIV-1 integration favors recurrent integration gene (RIG) targets and genic proviruses can confer cell survival in vivo. However, the relationship between initial RIG integrants and how these evolve in patients over time are unknown. To address these shortcomings, we built phenomenological models of random integration in silico, which were used to identify 3718 RIGs as well as 2150 recurrent avoided genes from 1.7 million integration sites across 10 in vitro datasets. Despite RIGs comprising only 13% of human genes, they harbored 70% of genic HIV-1 integrations across in vitro and patient-derived datasets. Although previously reported to associate with super-enhancers, RIGs tracked more strongly with speckle-associated domains. While depletion of the integrase cofactor LEDGF/p75 significantly reduced recurrent HIV-1 integration in vitro, LEDGF/p75 primarily occupied non-speckle-associated regions of chromatin, suggesting a previously unappreciated dynamic aspect of LEDGF/p75 functionality in HIV-1 integration targeting. Finally, we identified only six genes from patient samples—BACH2, STAT5B, MKL1, MKL2, IL2RB and MDC1—that displayed enriched integration targeting frequencies and harbored proviruses that likely contributed to cell survival. Thus, despite the known preference of HIV-1 to target cancer-related genes for integration, we conclude that genic proviruses play a limited role to directly affect cell proliferation in vivo.
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影响因子：
16.6
作者：
Cesana D;Santoni de Sio FR;Rudilosso L;Gallina P;Calabria A;Beretta S;Merelli I;Bruzzesi E;Passerini L;Nozza S;Vicenzi E;Poli G;Gregori S;Tambussi G;Montini E
通讯作者：
Montini E
影响因子：
6.7
作者：
Coffin JM;Bale MJ;Wells D;Guo S;Luke B;Zerbato JM;Sobolewski MD;Sia T;Shao W;Wu X;Maldarelli F;Kearney MF;Mellors JW;Hughes SH
通讯作者：
Hughes SH
影响因子：
14.9
作者：
De Rijck J;Bartholomeeusen K;Ceulemans H;Debyser Z;Gijsbers R
通讯作者：
Gijsbers R
影响因子：
4.8
作者：
Cherepanov, P;Maertens, G;Debyser, Z
通讯作者：
Debyser, Z
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS