The FAcilitates Chromatin Transcription complex regulates the ratio of glycolysis to oxidative phosphorylation in neural stem cells.

IF 5.3 2区 生物学 Q2 CELL BIOLOGY Journal of Molecular Cell Biology Pub Date : 2024-09-30 DOI:10.1093/jmcb/mjae017
Yuhan Lou, Litao Wu, Wanlin Cai, Huan Deng, Rong Sang, Shanshan Xie, Xiao Xu, Xin Yuan, Cheng Wu, Man Xu, Wanzhong Ge, Yongmei Xi, Xiaohang Yang
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Abstract

Defects in the FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone composed of SSRP1 and SUPT16H, are implicated in intellectual disability. Here, we reveal that the FACT complex promotes glycolysis and sustains the correct cell fate of neural stem cells/neuroblasts in the Drosophila 3rd instar larval central brain. We show that the FACT complex binds to the promoter region of the estrogen-related receptor (ERR) gene and positively regulates ERR expression. ERR is known to act as an aerobic glycolytic switch by upregulating the enzymes required for glycolysis. Dysfunction of the FACT complex leads to the downregulation of ERR transcription, resulting in a decreased ratio of glycolysis to oxidative phosphorylation (G/O) in neuroblasts. Consequently, neuroblasts exhibit smaller cell sizes, lower proliferation potential, and altered cell fates. Overexpression of ERR or suppression of mitochondrial oxidative phosphorylation in neuroblasts increases the relative G/O ratio and rescues defective phenotypes caused by dysfunction of the FACT complex. Thus, the G/O ratio, mediated by the FACT complex, plays a crucial role in neuroblast cell fate maintenance. Our study may shed light on the mechanism by which mutations in the FACT complex lead to intellectual disability in humans.

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FAcilitates 染色质转录复合物调节神经干细胞中糖酵解与氧化磷酸化的比例。
由 SSRP1 和 SUPT16H 组成的组蛋白伴侣--FAcilitates Chromatin Transcription (FACT) 复合物的缺陷与智力残疾有关。在这里,我们揭示了 FACT 复合物能促进糖酵解,并维持果蝇三龄幼虫中枢大脑神经干细胞/神经母细胞正确的细胞命运。我们发现,FACT复合体与雌激素相关受体(ERR)基因的启动子区域结合,并正向调节ERR的表达。众所周知,ERR 通过上调糖酵解所需的酶,起到有氧糖酵解开关的作用。FACT 复合物功能失调会导致ERR转录下调,从而导致神经母细胞中糖酵解与氧化磷酸化(G/O)的比例下降。因此,神经母细胞表现出细胞体积变小、增殖潜力降低和细胞命运改变。在神经母细胞中过表达ERR或抑制线粒体氧化磷酸化可提高相对G/O比率,并挽救因FACT复合体功能障碍而导致的缺陷表型。因此,由FACT复合体介导的G/O比率在神经母细胞命运维持中起着至关重要的作用。我们的研究可能揭示了FACT复合体突变导致人类智力障碍的机制。
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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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