Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy.
Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy.
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DOI：
10.1016/j.celrep.2021.109410
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发表时间：
2021-07-20
期刊：
影响因子：
8.8
通讯作者：
Rai K
中科院分区：
文献类型：
--
作者：
Terranova CJ;Tang M;Maitituoheti M;Raman AT;Ghosh AK;Schulz J;Amin SB;Orouji E;Tomczak K;Sarkar S;Oba J;Creasy C;Wu CJ;Khan S;Lazcano R;Wani K;Singh A;Barrodia P;Zhao D;Chen K;Haydu LE;Wang WL;Lazar AJ;Woodman SE;Bernatchez C;Rai K
转移过程中染色质状态模式的动态演变，它们与真正的遗传驱动因素的关系，以及它们的治疗脆弱性尚不完全清楚。对46例黑色素瘤样本的组合染色质状态分析显示，NRAS突变与二价组蛋白H3赖氨酸27三甲基化(H3K27me3)和Polycomb抑制复合体2相关。转移过程中二价结构域的重新编程发生在间质表型的主转录因子上，包括ZEB1、Twist1和CDH1。通过药物抑制EZH2来解决二价性降低了黑色素瘤细胞的侵袭能力，并显著降低了体内的肿瘤负担，特别是在NRAS突变体中。与二价重编程一致的是，促转移基因和黑素细胞特异性细胞识别基因的表达增加与异常广泛的H3K4me3结构域有关，这表明这种表观遗传元件具有作用。总体而言，我们证明了二价区和宽域的重新编程代表了转移性黑色素瘤的关键表观遗传学改变，EZH2加MEK抑制可能为NRAS突变黑色素瘤患者提供一种有前途的治疗策略。Terranova等人。为黑色素瘤提供全面的表观基因组资源，包括284个染色质图谱。他们发现了二价区和宽域在促转移基因表达中的关键调控作用，并确定EZH2加MEK抑制是治疗NRAS突变黑色素瘤的一种策略。
The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients. Terranova et al. provide a comprehensive epigenome resource for melanoma encompassing 284 chromatin maps. They find key regulatory roles for bivalent and broad domains in expression of pro-metastatic genes and identify EZH2 plus MEK inhibition as a therapeutic strategy for NRAS mutant melanomas.
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影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
64.5
作者：
Benayoun BA;Pollina EA;Ucar D;Mahmoudi S;Karra K;Wong ED;Devarajan K;Daugherty AC;Kundaje AB;Mancini E;Hitz BC;Gupta R;Rando TA;Baker JC;Snyder MP;Cherry JM;Brunet A
通讯作者：
Brunet A
影响因子：
64.5
作者：
Ceccarelli M;Barthel FP;Malta TM;Sabedot TS;Salama SR;Murray BA;Morozova O;Newton Y;Radenbaugh A;Pagnotta SM;Anjum S;Wang J;Manyam G;Zoppoli P;Ling S;Rao AA;Grifford M;Cherniack AD;Zhang H;Poisson L;Carlotti CG Jr;Tirapelli DP;Rao A;Mikkelsen T;Lau CC;Yung WK;Rabadan R;Huse J;Brat DJ;Lehman NL;Barnholtz-Sloan JS;Zheng S;Hess K;Rao G;Meyerson M;Beroukhim R;Cooper L;Akbani R;Wrensch M;Haussler D;Aldape KD;Laird PW;Gutmann DH;TCGA Research Network;Noushmehr H;Iavarone A;Verhaak RG
通讯作者：
Verhaak RG
影响因子：
64.5
作者：
Cancer Genome Atlas Network
通讯作者：
Cancer Genome Atlas Network
影响因子：
64.5
作者：
Bernstein, BE;Mikkelsen, TS;Lander, ES
通讯作者：
Lander, ES