皮质类固醇诱导的 FKBP5 基因染色质环动态,Annals of the New York Academy of Sciences

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皮质类固醇诱导的 FKBP5 基因染色质环动态
Annals of the New York Academy of Sciences ( IF 4.1 ) Pub Date : 2023-10-05 , DOI: 10.1111/nyas.15064
Cheng Wang ₁ , Freek Manders _{1,

2} , Laszlo Groh _{1,

3} , Roel Oldenkamp _{1,

4} , Colin Logie ₁

Affiliation

FKBP5是一个 115 kb 长的糖皮质激素诱导基因，与精神疾病有关。为了研究FKBP5拓扑相关域 (TAD)染色质相互作用频率的复杂性，我们在基因启动子、增强子、内含子和 CTCF 环锚点附近部署了 15 个一对多染色质捕获视点。这揭示了包含FKBP5启动子及其增强子的“一个 TAD 一个基因”结构。FKBP5启动子及其两个糖皮质激素刺激的增强子在整个 TAD 中漫游，同时显示微妙的细胞类型特异性相互作用组。FKBP5 TAD 由两个嵌套的 CTCF 环组成，这两个环由FKBP5第八个内含子中的一个 CTCF 位点和位于其多腺苷酸化位点之外 61 kb 之外的另一个位点协调。环延伸与通过内含子 CTCF 位点的转录增加相关。这得到了有效的补偿，因为即使在高转录状态下短环也能恢复。FKBP5 TAD的边界由不同的 CTCF 位点模式组成，包含多个较小的基因，并且对糖皮质激素刺激具有弹性。有趣的是，两个FKBP5 TAD 边界都含有 H3K27me3 标记的异染色质块，可能会增强它们。我们提出，FKBP5表达变异背后的顺式作用遗传和表观遗传多态性可能位于由FKBP5 TAD、其左亚 TAD 及其两个边界组成的 240-kb 区域内。

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Corticosteroid-induced chromatin loop dynamics at the FKBP5 gene

FKBP5 is a 115-kb-long glucocorticoid-inducible gene implicated in psychiatric disorders. To investigate the complexities of chromatin interaction frequencies at the FKBP5 topologically associated domain (TAD), we deployed 15 one-to-all chromatin capture viewpoints near gene promoters, enhancers, introns, and CTCF-loop anchors. This revealed a “one-TAD-one-gene” structure encompassing the FKBP5 promoter and its enhancers. The FKBP5 promoter and its two glucocorticoid-stimulated enhancers roam the entire TAD while displaying subtle cell type–specific interactomes. The FKBP5 TAD consists of two nested CTCF loops that are coordinated by one CTCF site in the eighth intron of FKBP5 and another beyond its polyadenylation site, 61 kb further. Loop extension correlates with transcription increases through the intronic CTCF site. This is efficiently compensated for, since the short loop is restored even under high transcription regimes. The boundaries of the FKBP5 TAD consist of divergent CTCF site patterns, harbor multiple smaller genes, and are resilient to glucocorticoid stimulation. Interestingly, both FKBP5 TAD boundaries harbor H3K27me3-marked heterochromatin blocks that may reinforce them. We propose that cis-acting genetic and epigenetic polymorphisms underlying FKBP5 expression variation are likely to reside within a 240-kb region that consists of the FKBP5 TAD, its left sub-TAD, and both its boundaries.

更新日期：2023-10-05

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