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BCL7A-containing SWI/SNF/BAF complexes modulate mitochondrial bioenergetics during neural progenitor differentiation
The EMBO Journal ( IF 9.4 ) Pub Date : 2022-10-28 , DOI: 10.15252/embj.2022110595
Lena Wischhof 1 , Hang-Mao Lee 1 , Janine Tutas 1 , Clemens Overkott 1 , Eileen Tedt 1 , Miriam Stork 1 , Michael Peitz 2, 3 , Oliver Brüstle 2 , Thomas Ulas 4 , Kristian Händler 4 , Joachim L Schultze 4, 5 , Dan Ehninger 1 , Pierluigi Nicotera 1 , Paolo Salomoni 1 , Daniele Bano 1
Affiliation  

Mammalian SWI/SNF/BAF chromatin remodeling complexes influence cell lineage determination. While the contribution of these complexes to neural progenitor cell (NPC) proliferation and differentiation has been reported, little is known about the transcriptional profiles that determine neurogenesis or gliogenesis. Here, we report that BCL7A is a modulator of the SWI/SNF/BAF complex that stimulates the genome-wide occupancy of the ATPase subunit BRG1. We demonstrate that BCL7A is dispensable for SWI/SNF/BAF complex integrity, whereas it is essential to regulate Notch/Wnt pathway signaling and mitochondrial bioenergetics in differentiating NPCs. Pharmacological stimulation of Wnt signaling restores mitochondrial respiration and attenuates the defective neurogenic patterns observed in NPCs lacking BCL7A. Consistently, treatment with an enhancer of mitochondrial biogenesis, pioglitazone, partially restores mitochondrial respiration and stimulates neuronal differentiation of BCL7A-deficient NPCs. Using conditional BCL7A knockout mice, we reveal that BCL7A expression in NPCs and postmitotic neurons is required for neuronal plasticity and supports behavioral and cognitive performance. Together, our findings define the specific contribution of BCL7A-containing SWI/SNF/BAF complexes to mitochondria-driven NPC commitment, thereby providing a better understanding of the cell-intrinsic transcriptional processes that connect metabolism, neuronal morphogenesis, and cognitive flexibility.

中文翻译:


含有 BCL7A 的 SWI/SNF/BAF 复合物在神经祖细胞分化过程中调节线粒体生物能



哺乳动物 SWI/SNF/BAF 染色质重塑复合物影响细胞谱系测定。虽然这些复合物对神经祖细胞(NPC)增殖和分化的贡献已有报道,但对于决定神经发生或胶质细胞生成的转录谱却知之甚少。在此,我们报告 BCL7A 是 SWI/SNF/BAF 复合物的调节剂,可刺激 ATP 酶亚基 BRG1 在全基因组范围内的占据。我们证明,BCL7A 对于 SWI/SNF/BAF 复合体的完整性是可有可无的,而在分化 NPC 时,它对于调节 Notch/Wnt 通路信号传导和线粒体生物能学至关重要。 Wnt 信号传导的药理学刺激可恢复线粒体呼吸并减弱在缺乏 BCL7A 的 NPC 中观察到的缺陷神经源性模式。一致地,用线粒体生物发生增强剂吡格列酮治疗可部分恢复线粒体呼吸并刺激 BCL7A 缺陷的 NPC 的神经元分化。使用条件性 BCL7A 敲除小鼠,我们发现 NPC 和有丝分裂后神经元中的 BCL7A 表达是神经元可塑性所必需的,并支持行为和认知表现。总之,我们的研究结果定义了包含 BCL7A 的 SWI/SNF/BAF 复合物对线粒体驱动的 NPC 承诺的具体贡献,从而更好地理解连接代谢、神经元形态发生和认知灵活性的细胞内在转录过程。
更新日期:2022-10-28
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