Lineage-Specific Genes Are Prominent DNA Damage Hotspots during Leukemic Transformation of B Cell Precursors.
Lineage-Specific Genes Are Prominent DNA Damage Hotspots during Leukemic Transformation of B Cell Precursors.
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DOI：
10.1016/j.celrep.2017.01.057
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发表时间：
2017-02-14
期刊：
影响因子：
8.8
通讯作者：
Feldhahn N
中科院分区：
文献类型：
--
作者：
Boulianne B;Robinson ME;May PC;Castellano L;Blighe K;Thomas J;Reid A;Müschen M;Apperley JF;Stebbing J;Feldhahn N
在人类白血病中，谱系特异性基因是缺失的主要靶点，淋巴特异性基因在淋巴细胞白血病中常受影响，而髓系特异性基因则在髓系白血病中常受影响。为探究谱系特异性改变的基础，我们通过染色质免疫沉淀测序（ChIP-seq）分析了表达致白血病癌基因的原代B细胞前体中的全基因组DNA损伤情况。我们鉴定出1000多个敏感区域，其中B谱系特异性基因是最主要的靶点。在B谱系基因处鉴定出的热点与DNA双链断裂（DNA-DSBs）相关，影响人类白血病中携带基因组损伤的基因，并与成功转化细胞中的异位缺失相关。此外，我们发现大多数鉴定出的区域与高表达基因的基因体重叠，并且在转化的B细胞前体中诱导髓系表型会促使髓系基因座出现新生DNA损伤。因此，我们证明了谱系特异性转录使转化的B细胞前体中的谱系特异性基因易发生DNA损伤，这很可能促使人类白血病中谱系特异性基因频繁发生改变。
B谱系基因是转化的B细胞前体中γH2AX标记的DNA损伤位点
γH2AX热点出现在高转录、H3K27ac标记的基因处
γH2AX热点与R环序列及同向/反向转录相关
转化的B细胞中髓系诱导会导致髓系基因座发生DNA损伤
B淋巴细胞白血病中B谱系特异性基因频繁发生改变。布里安等人表明，转化的B细胞前体在B谱系基因处表现出转录偶联的DNA损伤。同样，转化的B细胞从淋巴系向髓系的转变会诱导髓系基因座发生DNA损伤，这表明谱系特异性转录使谱系特异性基因易于发生后续改变，正如在人类白血病中所观察到的那样。
In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B cell precursors expressing leukemia-inducing oncogenes by ChIP-seq. We identified more than 1,000 sensitive regions, of which B lineage-specific genes constitute the most prominent targets. Identified hotspots at B lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletion in successfully transformed cells. Furthermore, we show that most identified regions overlap with gene bodies of highly expressed genes and that induction of a myeloid lineage phenotype in transformed B cell precursors promotes de novo DNA damage at myeloid loci. Hence, we demonstrate that lineage-specific transcription predisposes lineage-specific genes in transformed B cell precursors to DNA damage, which is likely to promote the frequent alteration of lineage-specific genes in human leukemia. B lineage genes are γH2AX-marked DNA damage sites in transformed B cell precursors γH2AX hotspots occur at highly transcribed, H3K27ac-marked genes γH2AX hotspots relate to R loop sequences and con/divergent transcription Myeloid lineage induction in transformed B cells causes DNA damage at myeloid loci B lineage-specific genes are frequently altered in B lymphoid leukemia. Boulianne et al. show that transformed B cell precursors exhibit transcription-coupled DNA damage at B lineage genes. Likewise, lymphoid-to-myeloid conversion of transformed B cells induces DNA damage at myeloid loci, suggesting that lineage-specific transcription predisposes lineage-specific genes to subsequent alterations as observed in human leukemia.