Altered hydroxymethylation is seen at regulatory regions in pancreatic cancer and regulates oncogenic pathways.
Altered hydroxymethylation is seen at regulatory regions in pancreatic cancer and regulates oncogenic pathways.
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DOI：
10.1101/gr.222794.117
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发表时间：
2017-11
期刊：
影响因子：
7
通讯作者：
Verma A
中科院分区：
文献类型：
--
作者：
Bhattacharyya S;Pradhan K;Campbell N;Mazdo J;Vasantkumar A;Maqbool S;Bhagat TD;Gupta S;Suzuki M;Yu Y;Greally JM;Steidl U;Bradner J;Dawlaty M;Godley L;Maitra A;Verma A
致癌途径的转录失调是癌症的标志，可能是由于表观遗传学改变。5-羟甲基胞嘧啶（5-hmC）是一种表观遗传修饰，尚未在胰腺癌中进行研究。在一组低传代胰腺癌细胞系、原发性患者来源的异种移植物和胰腺对照中，使用hmC-seal对5-hmC富集位点进行全基因组分析，结果显示肿瘤组织中的模式发生了显著改变。不同的羟甲基化区域优先影响已知的基因组调控区域，特别是与已知的H3 K4 me 1增强子重叠。此外，使用氧化亚硫酸氢盐测序进行胞嘧啶甲基化和羟甲基化的碱基对分辨率分析，并与胰腺癌和对照样品中ATAC-seq的染色质可及性和RNA-seq的基因表达相关。5-hmC在染色质的开放区域特异性富集，5-hmC的获得与同源转录物的上调相关，包括与胰腺肿瘤有关的许多致癌途径，如MYC、KRAS、VEGFA和BRD 4。具体而言，BRD 4过表达，并在大多数肿瘤样本的增强子区域获得5-hmC。在功能上，在BRD 4启动子处获得5-hmC与报告基因测定和原始样品中转录本表达的增加相关。此外，阻断BRD 4可抑制胰腺癌的体内生长。总之，5-hmC的重新分布和优先富集在致癌增强子是一种新的调节机制，在人类胰腺癌。
Transcriptional deregulation of oncogenic pathways is a hallmark of cancer and can be due to epigenetic alterations. 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC-enriched loci with hmC-seal was conducted in a cohort of low-passage pancreatic cancer cell lines, primary patient-derived xenografts, and pancreatic controls and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected known regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers. Furthermore, base pair resolution analysis of cytosine methylation and hydroxymethylation with oxidative bisulfite sequencing was conducted and correlated with chromatin accessibility by ATAC-seq and gene expression by RNA-seq in pancreatic cancer and control samples. 5-hmC was specifically enriched at open regions of chromatin, and gain of 5-hmC was correlated with up-regulation of the cognate transcripts, including many oncogenic pathways implicated in pancreatic neoplasia, such as MYC, KRAS, VEGFA, and BRD4. Specifically, BRD4 was overexpressed and acquired 5-hmC at enhancer regions in the majority of neoplastic samples. Functionally, acquisition of 5-hmC at BRD4 promoter was associated with increase in transcript expression in reporter assays and primary samples. Furthermore, blockade of BRD4 inhibited pancreatic cancer growth in vivo. In summary, redistribution of 5-hmC and preferential enrichment at oncogenic enhancers is a novel regulatory mechanism in human pancreatic cancer.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
21.3
作者：
Etchegaray JP;Chavez L;Huang Y;Ross KN;Choi J;Martinez-Pastor B;Walsh RM;Sommer CA;Lienhard M;Gladden A;Kugel S;Silberman DM;Ramaswamy S;Mostoslavsky G;Hochedlinger K;Goren A;Rao A;Mostoslavsky R
通讯作者：
Mostoslavsky R
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
64.8
作者：
De Raedt, Thomas;Beert, Eline;Cichowski, Karen
通讯作者：
Cichowski, Karen
影响因子：
64.8
作者：
Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.