Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia.
Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia.
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DOI：
10.1038/s41598-021-87890-9
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发表时间：
2021-04-15
影响因子：
4.6
通讯作者：
Ding W
中科院分区：
文献类型：
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作者：
Tian S;Zhang H;Zhang P;Kalmbach M;Lee JH;Ordog T;Hampel PJ;Call TG;Witzig TE;Kay NE;Klee EW;Slager SL;Yan H;Ding W
T细胞幼淋巴细胞白血病（T-PLL）是一种罕见的疾病，具有侵袭性的临床过程。细胞遗传学分析、全外显子组和全基因组测序已经确定了T-PLL的主要结构改变，包括倒位、易位和拷贝数变异。在编码染色质调节因子和JAK-STAT信号通路的基因中也发现了复发性体细胞突变。表观遗传改变是许多癌症的标志。然而，全基因组的表观基因组谱还没有在T-PLL的报道，限制了其致癌机制的研究。我们假设表观遗传机制也在T-PLL发病机制中起关键作用。为了系统地验证这一假设，我们使用H3 K4 me 3和H3 K27 ac ChIP-seq以及T-PLL患者和健康个体的RNA-seq数据生成了调控区的全基因组图谱。我们发现T-PLL中下调的基因主要与防御反应、免疫系统或适应性免疫反应有关，而上调的基因则在发育过程中富集，同时也与WNT信号通路有关，在细胞命运决定中起重要作用。特别地，我们的分析揭示了T-PLL中调控景观的全局改变，其中差异峰高度富集免疫相关转录因子的结合基序，支持癌基因和参与DNA损伤反应和T细胞活化的基因的表观遗传调控。总之，我们的工作揭示了T-PLL中表观遗传失调的因果作用。
T cell prolymphocytic leukemia (T-PLL) is a rare disease with aggressive clinical course. Cytogenetic analysis, whole-exome and whole-genome sequencing have identified primary structural alterations in T-PLL, including inversion, translocation and copy number variation. Recurrent somatic mutations were also identified in genes encoding chromatin regulators and those in the JAK-STAT signaling pathway. Epigenetic alterations are the hallmark of many cancers. However, genome-wide epigenomic profiles have not been reported in T-PLL, limiting the mechanistic study of its carcinogenesis. We hypothesize epigenetic mechanisms also play a key role in T-PLL pathogenesis. To systematically test this hypothesis, we generated genome-wide maps of regulatory regions using H3K4me3 and H3K27ac ChIP-seq, as well as RNA-seq data in both T-PLL patients and healthy individuals. We found that genes down-regulated in T-PLL are mainly associated with defense response, immune system or adaptive immune response, while up-regulated genes are enriched in developmental process, as well as WNT signaling pathway with crucial roles in cell fate decision. In particular, our analysis revealed a global alteration of regulatory landscape in T-PLL, with differential peaks highly enriched for binding motifs of immune related transcription factors, supporting the epigenetic regulation of oncogenes and genes involved in DNA damage response and T-cell activation. Together, our work reveals a causal role of epigenetic dysregulation in T-PLL.
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影响因子：
30.8
作者：
Liu Y;Easton J;Shao Y;Maciaszek J;Wang Z;Wilkinson MR;McCastlain K;Edmonson M;Pounds SB;Shi L;Zhou X;Ma X;Sioson E;Li Y;Rusch M;Gupta P;Pei D;Cheng C;Smith MA;Auvil JG;Gerhard DS;Relling MV;Winick NJ;Carroll AJ;Heerema NA;Raetz E;Devidas M;Willman CL;Harvey RC;Carroll WL;Dunsmore KP;Winter SS;Wood BL;Sorrentino BP;Downing JR;Loh ML;Hunger SP;Zhang J;Mullighan CG
通讯作者：
Mullighan CG
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：
30.8
作者：
Calderon, Diego;Nguyen, Michelle L. T.;Pritchard, Jonathan K.
通讯作者：
Pritchard, Jonathan K.
影响因子：
6.5
作者：
Lopez, Cristina;Bergmann, Anke K.;Siebert, Reiner
通讯作者：
Siebert, Reiner
影响因子：
64.8
作者：
通讯作者：
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