A brain-specific pgc1α fusion transcript affects gene expression and behavioural outcomes in mice.
A brain-specific pgc1α fusion transcript affects gene expression and behavioural outcomes in mice.
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DOI：
10.26508/lsa.202101122
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发表时间：
2021-12
影响因子：
4.4
通讯作者：
Woychik RP
中科院分区：
文献类型：
--
作者：
Lozoya OA;Xu F;Grenet D;Wang T;Stevanovic KD;Cushman JD;Hagler TB;Gruzdev A;Jensen P;Hernandez B;Riadi G;Moy SS;Santos JH;Woychik RP
这项研究表明，大脑特异的PGC1a融合亚型的缺失会导致小鼠基因上调和运动损伤，这表明大脑中的PGC1亚型之间存在功能差异。前列环素α是外周组织中的转录共激活因子，但其在大脑中的功能尚不清楚。在小鼠和人类中已经报道了多种脑特异性前列腺素C_1α亚型，包括两个带有非编码重复序列的融合转录本(FT)，但它们的功能尚不清楚。FTs起始于参考启动子上游的一个简单序列重复位点∼570kb；其中一个还包括一段短的散布的核元素(正弦)。利用公开获得的基因组学数据，我们在这里证明了正弦FT是神经元中Pgc1α的主要形式。此外，小鼠的Sine突变导致了行为表型的改变，并显著上调了雌性小脑的基因表达，而不是雄性小脑。令人惊讶的是，这些基因主要参与神经传递，与经典的线粒体或抗氧化程序联系不大。这些数据扩大了我们对Pgc1α在神经生理学中的作用的认识，并表明不同的亚型可能具有不同的功能。他们还强调了在出于治疗目的调节大脑中Pgc1α水平之前需要进一步研究的必要性。
This study shows that loss of a brain-specific fusion isoform of PGC1a leads to up-regulation of genes and motor impairments in mice, suggesting functional differences between PGC1 isoforms in the brain. PGC1α is a transcriptional coactivator in peripheral tissues, but its function in the brain remains poorly understood. Various brain-specific Pgc1α isoforms have been reported in mice and humans, including two fusion transcripts (FTs) with non-coding repetitive sequences, but their function is unknown. The FTs initiate at a simple sequence repeat locus ∼570 Kb upstream from the reference promoter; one also includes a portion of a short interspersed nuclear element (SINE). Using publicly available genomics data, here we show that the SINE FT is the predominant form of Pgc1α in neurons. Furthermore, mutation of the SINE in mice leads to altered behavioural phenotypes and significant up-regulation of genes in the female, but not male, cerebellum. Surprisingly, these genes are largely involved in neurotransmission, having poor association with the classical mitochondrial or antioxidant programs. These data expand our knowledge on the role of Pgc1α in neuronal physiology and suggest that different isoforms may have distinct functions. They also highlight the need for further studies before modulating levels of Pgc1α in the brain for therapeutic purposes.