Profiling chromatin accessibility in pediatric acute lymphoblastic leukemia identifies subtype-specific chromatin landscapes and gene regulatory networks.
Profiling chromatin accessibility in pediatric acute lymphoblastic leukemia identifies subtype-specific chromatin landscapes and gene regulatory networks.
复制标题
小儿急性淋巴细胞白血病中的染色质可及性鉴定亚型特异性染色质景观和基因调节网络。
DOI：
10.1038/s41375-021-01209-1
复制
发表时间：
2021-11
期刊：
影响因子：
11.4
通讯作者：
Savic D
中科院分区：
文献类型：
--
作者：
Diedrich JD;Dong Q;Ferguson DC;Bergeron BP;Autry RJ;Qian M;Yang W;Smith C;Papizan JB;Connelly JP;Hagiwara K;Crews KR;Pruett-Miller SM;Pui CH;Yang JJ;Relling MV;Evans WE;Savic D
急性淋巴细胞白血病（ALL）是一种造血系统恶性肿瘤，由主要以非整倍体或反复染色体重排为特征的分子亚型组成。尽管关于ALL转录组和甲基化组的信息广泛，但对ALL染色质景观的理解有限。因此，我们在24个原发性ALL细胞生物标本中绘制了可接近的染色质，包括三种常见的分子亚型（DUX 4/ERG，ETV 6-RUNX 1和超二倍体），这些细胞来自圣裘德儿童研究医院的患者。我们的研究结果强调了ALL中广泛的染色质重编程，包括识别出由遗传变异额外调节的ALL亚型特异性染色质景观。ALL和正常B细胞之间的染色质可及性差异暗示了B细胞抑制的染色质结构域的激活，并详细说明了ALL中正常B细胞发育的破坏。在ALL亚型中，我们发现了碱性螺旋-环-螺旋、同源结构域和激活蛋白1转录因子在促进亚型特异性染色质可及性和不同基因调控网络中的作用。除了染色质亚型特异性，我们还鉴定了超过3500种DNA序列变异，这些变异改变了ALL染色质景观，并导致染色质可及性的个体间变异。总的来说，我们的数据表明，亚型特异性染色质景观和基因调控网络影响ALL生物学，并有助于ALL亚型之间的转录组差异。
Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy comprised of molecular subtypes largely characterized by aneuploidy or recurring chromosomal rearrangements. Despite extensive information on the ALL transcriptome and methylome, there is limited understanding of the ALL chromatin landscape. We therefore mapped accessible chromatin in 24 primary ALL cell biospecimens comprising three common molecular subtypes (DUX4/ERG, ETV6-RUNX1 and hyperdiploid) from patients treated at St. Jude Children’s Research Hospital. Our findings highlight extensive chromatin reprogramming in ALL, including the identification ALL subtype-specific chromatin landscapes that are additionally modulated by genetic variation. Chromatin accessibility differences between ALL and normal B-cells implicate the activation of B-cell repressed chromatin domains and detail the disruption of normal B-cell development in ALL. Among ALL subtypes, we uncovered roles for basic helix-loop-helix, homeodomain and activator protein 1 transcription factors in promoting subtype-specific chromatin accessibility and distinct gene regulatory networks. In addition to chromatin subtype-specificity, we further identified over 3500 DNA sequence variants that alter the ALL chromatin landscape and contribute to inter-individual variability in chromatin accessibility. Collectively, our data suggest that subtype-specific chromatin landscapes and gene regulatory network impact ALL biology and contribute to transcriptomic differences among ALL subtypes.
登录
查看更多内容
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：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
30.8
作者：
Calderon, Diego;Nguyen, Michelle L. T.;Pritchard, Jonathan K.
通讯作者：
Pritchard, Jonathan K.
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
30.8
作者：
Corces, M. Ryan;Buenrostro, Jason D.;Wu, Beijing;Greenside, Peyton G.;Chan, Steven M.;Koenig, Julie L.;Snyder, Michael P.;Pritchard, Jonathan K.;Kundaje, Anshul;Gkeenleaf, William J.;Majeti, Ravindra;Chang, Howard Y.
通讯作者：
Chang, Howard Y.