Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements.
Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements.
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DOI：
10.15252/msb.202110473
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发表时间：
2022-08
影响因子：
9.9
通讯作者：
中科院分区：
文献类型：
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脑源性神经营养因子 (BDNF) 诱导的神经元刺激会触发基因表达，这对于神经元存活、分化、突触可塑性、记忆形成和神经认知健康至关重要。然而，其在染色质调节中的作用尚不清楚。在这里，通过对 BDNF 刺激或去极化 (KCl) 后小鼠原代皮层神经元染色质可及性和转录的时间分析，我们确定了定义 BDNF 特异性染色质到基因表达程序的特征。增强子激活是 BDNF 处理神经元调节控制的早期事件，其中 bZIP 基序结合 Fos 蛋白率先打开染色质，并与共调节转录因子（同源框、EGR 和 CTCF）配合诱导转录。删除顺式调控序列会影响 BDNF 介导的 Arc 表达，这是突触可塑性的调节因子。 BDNF 诱导的可及区域与神经发育障碍相关基因的外显子优先使用和神经元复杂性状的遗传性有关，这在人类 iPSC 衍生的神经元中得到了验证。因此，我们使用比较基因组方法来剖析哺乳动物神经元刺激，提供 BDNF 介导的基因组调控特征的全面视图。动态多组学分析和比较基因组学用于剖析 BDNF 对神经元染色质的作用。提供了 BDNF 特异性调控特征的全面描述，从转录因子相互作用到复杂特征。
Neuronal stimulation induced by the brain‐derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF‐specific chromatin‐to‐gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF‐treated neurons, where the bZIP motif‐binding Fos protein pioneered chromatin opening and cooperated with co‐regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis‐regulatory sequences affect BDNF‐mediated Arc expression, a regulator of synaptic plasticity. BDNF‐induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder‐related genes and the heritability of neuronal complex traits, which were validated in human iPSC‐derived neurons. Thus, we provide a comprehensive view of BDNF‐mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal stimulation. Dynamic multi‐omic profiling and comparative genomics are used to dissect the role of BDNF on neuronal chromatin. A comprehensive description of BDNF‐specific regulatory features is provided, from transcription factor interactions to complex traits.
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影响因子：
64.5
作者：
de la Torre-Ubieta L;Stein JL;Won H;Opland CK;Liang D;Lu D;Geschwind DH
通讯作者：
Geschwind DH
影响因子：
64.8
作者：
Boix CA;James BT;Park YP;Meuleman W;Kellis M
通讯作者：
Kellis M
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
64.8
作者：
Ataman B;Boulting GL;Harmin DA;Yang MG;Baker-Salisbury M;Yap EL;Malik AN;Mei K;Rubin AA;Spiegel I;Durresi E;Sharma N;Hu LS;Pletikos M;Griffith EC;Partlow JN;Stevens CR;Adli M;Chahrour M;Sestan N;Walsh CA;Berezovskii VK;Livingstone MS;Greenberg ME
通讯作者：
Greenberg ME