染色体环域指导抗原受体基因的重组
Jiazhi Hu1, Yu Zhang1, Lijuan Zhao1
1Howard Hughes Medical Institute; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Cell
|November 24, 2015
概括
该RAG酶启动DNA断裂以进行V(D) J重组. 新的研究确定了RAG的众多"非目标"断裂,揭示了淋巴细胞中DNA修复和染色质组织的机制.
科学领域:
- 分子生物学
- 免疫学
- 遗传学
背景情况:
- 在发育中的淋巴细胞中,RAG酶对于启动V(D) J重组至关重要.
- V(D) J重组需要在特定的重组信号序列 (RSS) 进行精确的DNA断裂.
研究的目的:
- 识别和描述RAG产生的"目标外"DNA断裂.
- 了解在染色体域内调节RAG活动的机制.
主要方法:
- 在内源性和外源性RSS对中利用RAG产生的诱断裂.
- 分析了非目标断裂位置及其与CTCF绑定元素 (CBEs) 和循环域的关联.
- 研究了导向依赖和线性跟踪在RAG非目标活动中的作用.
- 研究了删除基于CBE的IgH位元对RAG活动分布的影响.
主要成果:
- 在CAC动机,RSS裂纹处发生的众多RAG脱.
- 目标之外的断裂在很大程度上局限于融合的CTCF绑定元件 (CBE) 边缘循环领域.
- 在大循环域内,RAG的目标外活动的方向依赖性被证明是线性跟踪.
- 发现染色体转移的主要RAG异位涉及循环内增强器的汇聚RSS对.
- 删除IgH位点的CBE元素改变了V(D) J重组域和RAG在/离目标分布.
结论:
- RAG活动在发育过程中集中,在染色体循环中的特定DNA动机中发生非目标断裂.
- 由CBE等元素调节的染色体域在利用和指导生物过程中发挥作用,例如V(D) J重组.
- 涉及循环域内线性跟踪的机制有助于对RAG目标外活动的空间调节.
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