Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.
Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.
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DOI：
10.1016/j.molcel.2021.04.015
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发表时间：
2021-05-20
期刊：
影响因子：
16
通讯作者：
Johnstone RW
中科院分区：
文献类型：
--
作者：
Hogg SJ;Motorna O;Cluse LA;Johanson TM;Coughlan HD;Raviram R;Myers RM;Costacurta M;Todorovski I;Pijpers L;Bjelosevic S;Williams T;Huskins SN;Kearney CJ;Devlin JR;Fan Z;Jabbari JS;Martin BP;Fareh M;Kelly MJ;Dupéré-Richer D;Sandow JJ;Feran B;Knight D;Khong T;Spencer A;Harrison SJ;Gregory G;Wickramasinghe VO;Webb AI;Taberlay PC;Bromberg KD;Lai A;Papenfuss AT;Smyth GK;Allan RS;Licht JD;Landau DA;Abdel-Wahab O;Shortt J;Vervoort SJ;Johnstone RW
为了分离组蛋白乙酰化对染色质可及性和转录输出的因果影响，我们在血液恶性肿瘤中急性抑制主要细胞赖氨酸乙酰转移酶P300和CBP后，使用了综合表观基因组学和转录组学分析。我们发现，催化P300/CBP抑制动态扰动稳态乙酰化动力学和抑制致癌的转录网络的情况下，染色质可及性的变化。CRISPR/Cas9筛选通过抵消乙酰化周转动力学将NCOR 1和HDAC 3转录共阻遏物鉴定为P300/CBP的主要拮抗剂。最后，H3 K27的脱乙酰化提供了相互甲基化转换的成核位点，这是一种可以通过伴随的KDM 6A和P300抑制在治疗上利用的特征。总体而言，这项研究表明，稳态组蛋白乙酰化-甲基化平衡的功能作为一个分子变阻器管理细胞转录，是适合作为一种抗癌方案的治疗开发。Hogg等人使用多模式基因组学来探索靶向组蛋白乙酰转移酶P300/CBP的治疗在癌症中的急性表观遗传和转录效应。催化性P300/CBP抑制选择性地损害关键致癌转录因子的表达，导致稳健的抗肿瘤应答，但在补偿性组蛋白甲基化转换之前保持固有可逆性。
To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR/Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300 inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen. Hogg et al. use multimodal genomics to explore the acute epigenetic and transcriptional effects of therapies targeting histone acetyltransferases P300/CBP in cancer. Catalytic P300/CBP inhibition selectively impairs expression of key oncogenic transcription factors, leading to robust anti-tumor responses, but remains inherently reversible prior to compensatory histone methylation switching.
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
16.8
作者：
Højfeldt JW;Laugesen A;Willumsen BM;Damhofer H;Hedehus L;Tvardovskiy A;Mohammad F;Jensen ON;Helin K
通讯作者：
Helin K
影响因子：
5.3
作者：
Guenther, MG;Barak, O;Lazar, MA
通讯作者：
Lazar, MA
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
8.8
作者：
Ezponda T;Dupéré-Richer D;Will CM;Small EC;Varghese N;Patel T;Nabet B;Popovic R;Oyer J;Bulic M;Zheng Y;Huang X;Shah MY;Maji S;Riva A;Occhionorelli M;Tonon G;Kelleher N;Keats J;Licht JD
通讯作者：
Licht JD