The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia.
The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia.
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DOI：
10.1038/s41591-018-0028-4
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发表时间：
2018-06
期刊：
影响因子：
82.9
通讯作者：
Martin-Subero JI
中科院分区：
文献类型：
--
作者：
Beekman R;Chapaprieta V;Russiñol N;Vilarrasa-Blasi R;Verdaguer-Dot N;Martens JHA;Duran-Ferrer M;Kulis M;Serra F;Javierre BM;Wingett SW;Clot G;Queirós AC;Castellano G;Blanc J;Gut M;Merkel A;Heath S;Vlasova A;Ullrich S;Palumbo E;Enjuanes A;Martín-García D;Beà S;Pinyol M;Aymerich M;Royo R;Puiggros M;Torrents D;Datta A;Lowy E;Kostadima M;Roller M;Clarke L;Flicek P;Agirre X;Prosper F;Baumann T;Delgado J;López-Guillermo A;Fraser P;Yaspo ML;Guigó R;Siebert R;Martí-Renom MA;Puente XS;López-Otín C;Gut I;Stunnenberg HG;Campo E;Martin-Subero JI
慢性淋巴细胞白血病(CLL)是一种常见的血液肿瘤，其潜在的表观遗传学改变仅被部分了解。在这里，我们分析了在正常B细胞分化的背景下，7个原发CLL的参考表观基因组和107个原发病例的调节染色质景观。我们发现，在正常的B细胞成熟过程中，CLL染色质景观在很大程度上受到不同的动力学因素的影响。除此之外，我们还根据IGHV的体细胞高突变水平，定义了在CLL中重新编程的调控元件的广泛目录及其主要的临床生物学亚型。我们发现IGHV突变的CLL比IGHV突变的CLL具有更多的活性和开放的染色质。此外，我们还发现CLL中的从头活性区域富含NFAT、FOX和TCF/LEF转录因子家族结合位点。虽然大多数基因改变与一致的表观遗传学特征无关，但具有MYD88突变和12三体的CLL显示出不同的染色质配置。此外，我们观察到IGHV突变的CLL中的非编码突变富含在可及染色质之外的H3K27ac相关调控元件中。总体而言，这项研究提供了CLL表观基因组的完整图景，确定了改变的调控元件的广泛网络，并阐明了疾病的遗传和表观遗传结构之间的关系。
Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B-cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B-cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
64.8
作者：
Jin, Fulai;Li, Yan;Dixon, Jesse R.;Selvaraj, Siddarth;Ye, Zhen;Lee, Ah Young;Yen, Chia-An;Schmitt, Anthony D.;Espinoza, Celso A.;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.8
作者：
通讯作者：
--
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：
11.4
作者：
Cahill, N.;Bergh, A-C;Rosenquist, R.
通讯作者：
Rosenquist, R.