Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements.
Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements.
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DOI：
10.1016/j.ajhg.2023.12.015
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发表时间：
2024-01
影响因子：
9.8
通讯作者：
B. Rogers;Ashlyn G. Anderson;Shelby N. Lauzon;M. N. Davis;Rebecca M. Hauser;Sydney C. Roberts;Ivan Rodriguez-Nunez;Katie Trausch-Lowther;Erin A. Barinaga;Paige I Hall;Matthew T Knuesel;Jared W Taylor;M. Mackiewicz;Brian S. Roberts;Sara J. Cooper;Lindsay F. Rizzardi;R. M. Myers;J. N. Cochran
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文献类型：
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作者：
B. Rogers;Ashlyn G. Anderson;Shelby N. Lauzon;M. N. Davis;Rebecca M. Hauser;Sydney C. Roberts;Ivan Rodriguez-Nunez;Katie Trausch-Lowther;Erin A. Barinaga;Paige I Hall;Matthew T Knuesel;Jared W Taylor;M. Mackiewicz;Brian S. Roberts;Sara J. Cooper;Lindsay F. Rizzardi;R. M. Myers;J. N. Cochran
tau蛋白病是一组由tau蛋白异常聚集所定义的神经退行性疾病，tau蛋白是由MAPT编码的微管相关蛋白。这种时间动态的表达模式表明MAPT的表达可能受分化细胞类型特异性转录因子和顺式调控元件的控制。鉴于MAPT表达与神经退行性疾病发病机制的相关性，这些元件的鉴定与理解疾病风险和发病机制相关。在这里，我们对NPC和分化的神经元中的H3 K27 ac和CTCF进行了染色质构象测定（HiC & Capture-C）、单核多组学（RNA-seq+ATAC-seq）、批量ATAC-seq和ChIP-seq，以提名候选调控元件（cCREs）。我们使用荧光素酶测定和CRISPR干扰（CRISPRi）实验来测定这些cCREs，以测量它们对MAPT表达的影响。最后，我们将cCRE注释整合到受神经退行性变影响的个体和对照受试者的遗传变异分析中。我们鉴定了MAPT的近端和远端调控元件，并证实了几个区域的调控功能，包括H1/H2单倍型倒位断点以外的三个着丝粒区域。我们还发现，与对照组相比，痴呆患者的克雷斯中罕见的和预测的破坏性遗传变异在名义上被耗尽，这与破坏MAPT增强子活性的变异，从而减少MAPT表达，可能对神经退行性疾病具有保护作用的假设一致。总的来说，这项研究提供了令人信服的证据，追求详细的知识克雷斯的基因的兴趣，以允许更好地了解疾病的风险。
Tauopathies are a group of neurodegenerative diseases defined by abnormal aggregates of tau, a microtubule-associated protein encoded byMAPT.MAPTexpression is near absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests thatMAPTexpression could be controlled by transcription factors andcis-regulatory elements specific to differentiated cell types. Given the relevance ofMAPTexpression to neurodegeneration pathogenesis, identification of such elements is relevant to understanding disease risk and pathogenesis. Here, we performed chromatin conformation assays (HiC & Capture-C), single-nucleus multiomics (RNA-seq+ATAC-seq), bulk ATAC-seq, and ChIP-seq for H3K27ac and CTCF in NPCs and differentiated neurons to nominate candidatecis-regulatory elements (cCREs). We assayed these cCREs using luciferase assays and CRISPR interference (CRISPRi) experiments to measure their effects onMAPTexpression. Finally, we integrated cCRE annotations into an analysis of genetic variation in neurodegeneration-affected individuals and control subjects. We identified both proximal and distal regulatory elements forMAPTand confirmed the regulatory function for several regions, including three regions centromeric toMAPTbeyond the H1/H2 haplotype inversion breakpoint. We also found that rare and predicted damaging genetic variation in nominated CREs was nominally depleted in dementia-affected individuals relative to control subjects, consistent with the hypothesis that variants that disruptMAPTenhancer activity, and thereby reducedMAPTexpression, may be protective against neurodegenerative disease. Overall, this study provides compelling evidence for pursuing detailed knowledge of CREs for genes of interest to permit better understanding of disease risk.