El-Daher Marie-Therese, Cagnard Nicolas, Gil Marine, Da Cruz Marie Chansel, Leveau Claire, Sepulveda Fernando, Zarhrate Mohammed, Tores Frédéric, Legoix Patricia, Baulande Sylvain, de Villartay Jean Pierre, Almouzni Geneviève, Quivy Jean-Pierre, Fischer Alain, de Saint Basile Geneviève
1Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris, France.
2Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris, France.
Cell Discov. 2018 Nov 13;4:61. doi: 10.1038/s41421-018-0061-y. eCollection 2018.
A loss-of-function mutation in tetratricopeptide repeat domain 7A (TTC7A) is a recently identified cause of human intestinal and immune disorders. However, clues to related underlying molecular dysfunctions remain elusive. It is now shown based on the study of TTC7A-deficient and wild-type cells that TTC7A is an essential nuclear protein. It binds to chromatin, preferentially at actively transcribed regions. Its depletion results in broad range of epigenomic changes at proximal and distal transcriptional regulatory elements and in altered control of the transcriptional program. Loss of WT_TTC7A induces general decrease in chromatin compaction, unbalanced cellular distribution of histones, higher nucleosome accessibility to nuclease digestion along with genome instability, and reduced cell viability. Our observations characterize for the first time unreported functions for TTC7A in the nucleus that exert a critical role in chromatin organization and gene regulation to safeguard healthy immune and intestinal status.
四肽重复结构域7A（TTC7A）的功能丧失突变是最近发现的人类肠道和免疫疾病的一个病因。然而，相关潜在分子功能障碍的线索仍然难以捉摸。基于对TTC7A缺陷型和野生型细胞的研究，现已表明TTC7A是一种必需的核蛋白。它与染色质结合，优先结合于活跃转录区域。其缺失导致近端和远端转录调控元件发生广泛的表观基因组变化，并改变转录程序的控制。野生型TTC7A的缺失导致染色质压缩普遍减少、组蛋白细胞分布失衡、核小体对核酸酶消化的可及性增加以及基因组不稳定，同时细胞活力降低。我们的观察首次揭示了TTC7A在细胞核中的未报道功能，这些功能在染色质组织和基因调控中发挥关键作用，以维护健康的免疫和肠道状态。
