Broad genic repression domains signify enhanced silencing of oncogenes.
Broad genic repression domains signify enhanced silencing of oncogenes.
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DOI：
10.1038/s41467-020-18913-8
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发表时间：
2020-11-03
影响因子：
16.6
通讯作者：
Chen K
中科院分区：
文献类型：
--
作者：
Zhao D;Zhang L;Zhang M;Xia B;Lv J;Gao X;Wang G;Meng Q;Yi Y;Zhu S;Tomoiaga AS;Lee MG;Cooke JP;Cao Q;Chen K
癌症是由一系列遗传和表观遗传改变引起的。大多数已知的致癌基因是通过癌症中的功能获得突变确定的，但对它们的表观遗传特征知之甚少。通过对来自bbbb8200对肿瘤-正常对的11596个表观基因组图谱和突变的综合分析，我们发现染色质上的广泛基因抑制域（BGRD）是癌基因的表观遗传特征。BGRD是抑制性组蛋白修饰H3K27me3的广泛富集区域，并与H3K9me3、H3K9me2和H3K27me2等多种其他抑制性标记进一步富集。此外，BGRD显示出广泛富集被抑制的顺式调控元件。BGRDs的缩短与转录抑制有关。癌基因上的BGRDs在正常细胞类型中往往是保守的。使用BGRDs定义的推定肿瘤促进基因和lncrna在实验中被证实是癌症表型所必需的。因此，BGRDs在癌症的表观遗传调控中发挥了关键作用，为不依赖突变发现癌基因提供了方向。表观遗传改变的基因可能在癌症病理生物学中发挥关键作用，但区分癌基因的表观遗传特征尚不清楚。在这里，作者确定了广泛的基因抑制域，由广泛的H3K27me3修饰定义，作为一种表观遗传特征，为发现潜在的致癌基因提供了突变无关的信息。
Cancers result from a set of genetic and epigenetic alterations. Most known oncogenes were identified by gain-of-function mutations in cancer, yet little is known about their epigenetic features. Through integrative analysis of 11,596 epigenomic profiles and mutations from >8200 tumor-normal pairs, we discover broad genic repression domains (BGRD) on chromatin as an epigenetic signature for oncogenes. A BGRD is a widespread enrichment domain of the repressive histone modification H3K27me3 and is further enriched with multiple other repressive marks including H3K9me3, H3K9me2, and H3K27me2. Further, BGRD displays widespread enrichment of repressed cis-regulatory elements. Shortening of BGRDs is linked to derepression of transcription. BGRDs at oncogenes tend to be conserved across normal cell types. Putative tumor-promoting genes and lncRNAs defined using BGRDs are experimentally verified as required for cancer phenotypes. Therefore, BGRDs play key roles in epigenetic regulation of cancer and provide a direction for mutation-independent discovery of oncogenes. Epigenetically altered genes can have a key role in cancer pathobiology but epigenetic signatures that distinguish oncogenes are not yet known. Here, the authors identify broad genic repression domains, defined by widespread H3K27me3 modification, as an epigenetic signature to provide mutation-independent information for discovery of potential oncogenes.
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影响因子：
64.5
作者：
Davoli T;Xu AW;Mengwasser KE;Sack LM;Yoon JC;Park PJ;Elledge SJ
通讯作者：
Elledge SJ
DOI：
10.1093/bioinformatics/btr490
发表时间：
2011-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Howe EA;Sinha R;Schlauch D;Quackenbush J
通讯作者：
Quackenbush J
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
28.2
作者：
Hammerman PS;Sos ML;Ramos AH;Xu C;Dutt A;Zhou W;Brace LE;Woods BA;Lin W;Zhang J;Deng X;Lim SM;Heynck S;Peifer M;Simard JR;Lawrence MS;Onofrio RC;Salvesen HB;Seidel D;Zander T;Heuckmann JM;Soltermann A;Moch H;Koker M;Leenders F;Gabler F;Querings S;Ansén S;Brambilla E;Brambilla C;Lorimier P;Brustugun OT;Helland A;Petersen I;Clement JH;Groen H;Timens W;Sietsma H;Stoelben E;Wolf J;Beer DG;Tsao MS;Hanna M;Hatton C;Eck MJ;Janne PA;Johnson BE;Winckler W;Greulich H;Bass AJ;Cho J;Rauh D;Gray NS;Wong KK;Haura EB;Thomas RK;Meyerson M
通讯作者：
Meyerson M
影响因子：
64.5
作者：
Castilla, LH;Wijmenga, C;Liu, PP
通讯作者：
Liu, PP