Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element.
Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element.
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DOI：
10.1084/jem.20141479
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发表时间：
2015-01-12
期刊：
影响因子：
--
通讯作者：
Oltz EM
中科院分区：
文献类型：
--
作者：
Majumder K;Koues OI;Chan EA;Kyle KE;Horowitz JE;Yang-Iott K;Bassing CH;Taniuchi I;Krangel MS;Oltz EM
Majumder等人探索了TCRβ多样性产生期间小鼠胸腺细胞发育早期Tcrb基因座的大规模成环结构。他们剖析了控制V到D-J重组的新型DNA调控元件，并在绝缘子区域内鉴定了一个位于远端的含CTCF的元件，该元件用作系链，有助于远端Vβ到Dβ-Jβ区域的成环并促进基因座收缩。第二个包含CTCF的元件，靠近Dβ-Jβ区域，作为边界，防止与Dβ-Jβ区域相关的活性染色质扩散。近端边界元件的移除损害了拴系元件的轨迹收缩能力。基因调控依赖于三维染色质构象的动态变化，其由复合调控和结构元件形成。然而，在染色体结构域内控制这种构象转换的机制仍然未知。我们确定了一种新的机制，顺式元件促进长程相互作用，诱导构象变化的TCRβ抗原受体基因座（Tcrb）的多样化至关重要。远端Vβ基因片段和高表达的DβJβ簇之间的关联，称为重组中心（RC），不依赖于增强子功能和V（D）J重组酶的募集。相反，我们发现Tcrb的组织特异性折叠依赖于位于RC上游的两个不同的架构元素。第一个是包含CTCF的元件，直接将Vβ阵列的远端部分拴系到RC。第二个元件是染色质屏障，其保护系链免受过度活跃的RC染色质的影响。当第二个元件被移除时，活性RC染色质向上游扩散，迫使系链充当新的屏障。CTCF元件获得屏障功能破坏了远端Vβ基因片段之间的接触，并显著改变了Tcrb库。我们的研究结果揭示了RC侧翼区的功能分离，其中锚定的远程重组必须封锁从过度活跃的RC景观的染色质屏障。
Majumder et al. explore the large-scale looping architecture of the Tcrb locus early in murine thymocyte development during the generation of TCRβ diversity. They dissect novel DNA regulatory elements controlling V to D-J recombination and identify within an insulator region a distally located CTCF-containing element functioning as a tether, which facilitates looping of distal Vβ to Dβ-Jβ regions and promotes locus contraction. A second CTCF-containing element, proximal to the Dβ-Jβ region, acts as a boundary, preventing the spread of active chromatin associated with Dβ-Jβ regions. Removal of the proximal boundary element impairs the locus contraction capabilities of the tethering element. Gene regulation relies on dynamic changes in three-dimensional chromatin conformation, which are shaped by composite regulatory and architectural elements. However, mechanisms that govern such conformational switches within chromosomal domains remain unknown. We identify a novel mechanism by which cis-elements promote long-range interactions, inducing conformational changes critical for diversification of the TCRβ antigen receptor locus (Tcrb). Association between distal Vβ gene segments and the highly expressed DβJβ clusters, termed the recombination center (RC), is independent of enhancer function and recruitment of V(D)J recombinase. Instead, we find that tissue-specific folding of Tcrb relies on two distinct architectural elements located upstream of the RC. The first, a CTCF-containing element, directly tethers distal portions of the Vβ array to the RC. The second element is a chromatin barrier that protects the tether from hyperactive RC chromatin. When the second element is removed, active RC chromatin spreads upstream, forcing the tether to serve as a new barrier. Acquisition of barrier function by the CTCF element disrupts contacts between distal Vβ gene segments and significantly alters Tcrb repertoires. Our findings reveal a separation of function for RC-flanking regions, in which anchors for long-range recombination must be cordoned off from hyperactive RC landscapes by chromatin barriers.
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