Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age.
Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age.
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DOI：
10.1111/acel.13499
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发表时间：
2021-11
期刊：
影响因子：
7.8
通讯作者：
Webb AE
中科院分区：
文献类型：
--
作者：
Maybury-Lewis SY;Brown AK;Yeary M;Sloutskin A;Dhakal S;Juven-Gershon T;Webb AE
成人和老年大脑中的神经干细胞（NSC）基本上是静止的，需要转录重编程才能重新进入细胞周期。然而，这些变化背后的机制以及它们如何随着年龄的变化而变化仍然不确定。在这里，我们确定了原代神经干/祖细胞在静止和激活状态下的染色质可及性差异。这些不同的细胞状态表现出共同的和独特的染色质谱，两者都与基因调控有关。特异于活化或静止的可分离染色质状态是由关键的促神经原性和静止因子结合的活性增强子。相反，共享位点富集与翻译和代谢相关的核心启动子元件。出乎意料的是，通过综合分析，我们发现在NSC激活过程中变得可访问的许多位点与基因抑制有关，并与促静止因子相关，揭示了一种可能保持静止再进入的新机制。此外，我们报告说，在老化的NSC中，与代谢和转录功能相关的染色质区域与关键的促静止转录因子结合，失去了可及性，这表明了年龄相关的NSC功能障碍的新机制。总之，我们的研究结果揭示了可访问的染色质状态如何调节NSC静止和激活之间的转录开关，以及这种开关如何随着年龄的增长而受到影响。成年哺乳动物大脑中的静止神经干细胞在激活增殖和神经发生时对其转录组进行了大修。我们报道了启动子和增强子处染色质动力学的不同模式支持干细胞活化，并且随着年龄的增长，关键代谢基因变得不那么容易获得。
Neural stem cells (NSCs) in the adult and aged brain are largely quiescent, and require transcriptional reprogramming to re‐enter the cell cycle. However, the mechanisms underlying these changes and how they are altered with age remain undefined. Here, we identify the chromatin accessibility differences between primary neural stem/progenitor cells in quiescent and activated states. These distinct cellular states exhibit shared and unique chromatin profiles, both associated with gene regulation. Accessible chromatin states specific to activation or quiescence are active enhancers bound by key pro‐neurogenic and quiescence factors. In contrast, shared sites are enriched for core promoter elements associated with translation and metabolism. Unexpectedly, through integrated analysis, we find that many sites that become accessible during NSC activation are linked to gene repression and associated with pro‐quiescence factors, revealing a novel mechanism that may preserve quiescence re‐entry. Furthermore, we report that in aged NSCs, chromatin regions associated with metabolic and transcriptional functions bound by key pro‐quiescence transcription factors lose accessibility, suggesting a novel mechanism of age‐associated NSC dysfunction. Together, our findings reveal how accessible chromatin states regulate the transcriptional switch between NSC quiescence and activation, and how this switch is affected with age. Quiescent neural stem cells in the adult mammalian brain overhaul their transcriptome as they activate for proliferation and neurogenesis. We report that distinct modes of chromatin dynamics at promoters and enhancers support stem cell activation, and that key metabolic genes become less accessible with age.
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影响因子：
16.2
作者：
Beckervordersandforth R;Ebert B;Schäffner I;Moss J;Fiebig C;Shin J;Moore DL;Ghosh L;Trinchero MF;Stockburger C;Friedland K;Steib K;von Wittgenstein J;Keiner S;Redecker C;Hölter SM;Xiang W;Wurst W;Jagasia R;Schinder AF;Ming GL;Toni N;Jessberger S;Song H;Lie DC
通讯作者：
Lie DC
降低的NRF2表达介导了关键的中年期间神经干细胞功能的下降。
影响因子：
7.8
作者：
Corenblum MJ;Ray S;Remley QW;Long M;Harder B;Zhang DD;Barnes CA;Madhavan L
通讯作者：
Madhavan L
影响因子：
4.6
作者：
Daynac M;Morizur L;Chicheportiche A;Mouthon MA;Boussin FD
通讯作者：
Boussin FD
影响因子：
7
作者：
Beagan JA;Duong MT;Titus KR;Zhou L;Cao Z;Ma J;Lachanski CV;Gillis DR;Phillips-Cremins JE
通讯作者：
Phillips-Cremins JE
影响因子：
4.5
作者：
Audesse, Amanda J.;Dhakal, Shleshma;Webb, Ashley E.
通讯作者：
Webb, Ashley E.