Mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation
Mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation
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DOI：
10.1073/pnas.1200106109
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发表时间：
2012-07-03
影响因子：
11.1
通讯作者：
Casellas, Rafael
中科院分区：
文献类型：
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作者：
Kovalchuk, Alexander L.;Ansarah-Sobrinho, Camilo;Casellas, Rafael
人类伯基特淋巴瘤分为两种主要的临床变体：地方性形式，影响感染疟疾和EB病毒的非洲儿童，以及散发形式，分布在世界其他地区。然而，尽管零星易位从5'近端调控元件处将Myc斩首，但大多数地方性事件发生在距离Myc数百个酶处。这些重排的起源以及它们如何在如此远的距离解除癌基因的调控仍不清楚。我们在这里概括地方性伯基特淋巴瘤样易位浆细胞瘤从尿嘧啶N-糖基化酶和激活诱导的胞苷脱氨酶缺陷小鼠。使用乙酰化组蛋白H3赖氨酸9染色质免疫沉淀测序方法绘制易位断点揭示了Myc或相关癌基因Mycn上游350 kb处的Igh融合。对肿瘤细胞中的表观遗传标记、PolII募集和转录的综合分析表明，3' Igh增强子（Ea）极大地将类似于450 kb的染色质重塑成易位序列，导致显著的聚合酶占据和组成性癌基因表达。我们表明，这种远程表观遗传重编程是成正比的物理相互作用的E α易位位点。因此，我们的研究揭示了IG 3'增强子的表观遗传重塑的程度，并为地方性伯基特淋巴瘤中易位癌基因的长距离失调提供了理论基础。这些数据也揭示了地方性染色体重排的起源。
Human Burkitt lymphomas are divided into two main clinical variants: the endemic form, affecting African children infected with malaria and the Epstein-Barr virus, and the sporadic form, distributed across the rest of the world. However, whereas sporadic translocations decapitate Myc from 5' proximal regulatory elements, most endemic events occur hundreds of kilobases away from Myc. The origin of these rearrangements and how they deregulate oncogenes at such distances remain unclear. We here recapitulate endemic Burkitt lymphoma-like translocations in plasmacytomas from uracil N-glycosylase and activation-induced cytidine deaminase-deficient mice. Mapping of translocation breakpoints using an acetylated histone H3 lysine 9 chromatin immunoprecipitation sequencing approach reveals Igh fusions up to similar to 350 kb upstream of Myc or the related oncogene Mycn. A comprehensive analysis of epigenetic marks, PolII recruitment, and transcription in tumor cells demonstrates that the 3' Igh enhancer (Ea) vastly remodels similar to 450 kb of chromatin into translocated sequences, leading to significant polymerase occupancy and constitutive oncogene expression. We show that this long-range epigenetic reprogramming is directly proportional to the physical interaction of E alpha with translocated sites. Our studies thus uncover the extent of epigenetic remodeling by Ig 3' enhancers and provide a rationale for the long-range deregulation of translocated oncogenes in endemic Burkitt lymphomas. The data also shed light on the origin of endemic-like chromosomal rearrangements.