Regulation of DNA replication within the immunoglobulin heavy-chain locus during B cell commitment.
Regulation of DNA replication within the immunoglobulin heavy-chain locus during B cell commitment.
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DOI：
10.1371/journal.pbio.1001360
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发表时间：
2012-07
期刊：
影响因子：
9.8
通讯作者：
Norio P
中科院分区：
文献类型：
--
作者：
Demczuk A;Gauthier MG;Veras I;Kosiyatrakul S;Schildkraut CL;Busslinger M;Bechhoefer J;Norio P
哺乳动物染色体复制的时间顺序似乎与它们的功能组织有关，但在细胞分化过程中建立和修改这种顺序的过程在很大程度上仍然未知。在这里，我们研究了免疫球蛋白基因座的复制如何在骨髓前B细胞进行B细胞定型中启动、进行和终止。我们发现，DNA复制的许多方面可以定量解释的机制，涉及随机发射的起源（跨越S期和Igh基因座）和广泛的变化，其发射率（沿着的轨迹）。起源的发射率显示跨越数十至数百个酶的Igh结构域的高度协调，这是在简单的真核生物中未观察到的现象。域大小和发射率的差异决定了复制的时间顺序。在B细胞定型过程中，B细胞特异性因子Pax 5的表达通过改变各种Igh结构域（特别是含有Pax 5结合位点的结构域）内的起始发射速率而急剧改变复制的时间顺序。我们认为，在Igh CH-3′RR结构域中，Pax 5主要通过控制复制前复合物组装下游的事件，负责建立和维持高速率的原点放电。每当哺乳动物细胞复制其基因组为细胞分裂做准备时，它就会激活数千个所谓的“DNA复制起点”。基因组的及时和完整复制取决于起源激活的精心编排，当细胞分化以执行特定功能时，起源激活被修改。我们目前缺乏一个普遍接受的起源调节模型，可以解释复杂的真核生物中的复制动力学。在这里，我们研究了小鼠免疫球蛋白重链基因座，基因组的抗体编码部分之一，当产生抗体的B细胞在骨髓中分化时，其起源改变活性。我们发现，DNA复制的起始，进展和终止的多个方面可以用数学解释的随机发射的起点和两个独立的变量之间的相互作用：复制叉的进展速度和发射率的起点沿着的轨迹。在B细胞分化过程中，起点放电的速率沿基因座沿着变化很大，因此是建立复制时间顺序的主导因素。一种叫做Pax 5的分化因子可以通过改变基因座各个部分的起始点发射速率来改变复制的时间顺序。
The temporal order of replication of mammalian chromosomes appears to be linked to their functional organization, but the process that establishes and modifies this order during cell differentiation remains largely unknown. Here, we studied how the replication of the Igh locus initiates, progresses, and terminates in bone marrow pro-B cells undergoing B cell commitment. We show that many aspects of DNA replication can be quantitatively explained by a mechanism involving the stochastic firing of origins (across the S phase and the Igh locus) and extensive variations in their firing rate (along the locus). The firing rate of origins shows a high degree of coordination across Igh domains that span tens to hundreds of kilobases, a phenomenon not observed in simple eukaryotes. Differences in domain sizes and firing rates determine the temporal order of replication. During B cell commitment, the expression of the B-cell-specific factor Pax5 sharply alters the temporal order of replication by modifying the rate of origin firing within various Igh domains (particularly those containing Pax5 binding sites). We propose that, within the Igh CH-3′RR domain, Pax5 is responsible for both establishing and maintaining high rates of origin firing, mostly by controlling events downstream of the assembly of pre-replication complexes. Each time a mammalian cell duplicates its genome in preparation for cell division it activates thousands of so called “DNA origins of replication.” The timely and complete duplication of the genome depends on careful orchestration of origin activation, which is modified when cells differentiate to perform a specific function. We currently lack a universally accepted model of origin regulation that can explain the replication dynamics in complex eukaryotes. Here, we studied the mouse immunoglobulin heavy-chain locus, one of the antibody-encoding portions of the genome, where origins change activity when antibody-producing B cells differentiate in the bone marrow. We show that multiple aspects of DNA replication initiation, progression, and termination can be explained mathematically by the interplay between randomly firing origins and two independent variables: the speed of progression of replication forks and the firing rate of origins along the locus. The rate of origin firing varies extensively along the locus during B cell differentiation and, thus, is a dominant factor in establishing the temporal order of replication. A differentiation factor called Pax5 can alter the temporal order of replication by modifying the rate of origin firing across various parts of the locus.
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影响因子：
4.3
作者：
Guilbaud G;Rappailles A;Baker A;Chen CL;Arneodo A;Goldar A;d'Aubenton-Carafa Y;Thermes C;Audit B;Hyrien O
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作者：
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作者：
Kalejta, RF;Li, X;Hamlin, JL
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