The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
Transl Psychiatry. 2022 Aug 8;12(1):319. doi: 10.1038/s41398-022-02053-2.
Bromodomain containing 1 (BRD1) encodes an epigenetic regulator that controls the expression of genetic networks linked to mental illness. BRD1 is essential for normal brain development and its role in psychopathology has been demonstrated in genetic and preclinical studies. However, the neurobiology that bridges its molecular and neuropathological effects remains poorly explored. Here, using publicly available datasets, we find that BRD1 targets nuclear genes encoding mitochondrial proteins in cell lines and that modulation of BRD1 expression, irrespective of whether it is downregulation or upregulation of one or the other existing BRD1 isoforms (BRD1-L and BRD1-S), leads to distinct shifts in the expression profile of these genes. We further show that the expression of nuclear genes encoding mitochondrial proteins is negatively correlated with the expression of BRD1 mRNA during human brain development. In accordance, we identify the key gate-keeper of mitochondrial metabolism, Peroxisome proliferator-activated receptor (PPAR) among BRD1's co-transcription factors and provide evidence that BRD1 acts as a co-repressor of PPAR-mediated transcription. Lastly, when using quantitative PCR, mitochondria-targeted fluorescent probes, and the Seahorse XFe96 Analyzer, we demonstrate that modulation of BRD1 expression in cell lines alters mitochondrial physiology (mtDNA content and mitochondrial mass), metabolism (reducing power), and bioenergetics (among others, basal, maximal, and spare respiration) in an expression level- and isoform-dependent manner. Collectively, our data suggest that BRD1 is a transcriptional regulator of nuclear-encoded mitochondrial proteins and that disruption of BRD1's genomic actions alters mitochondrial functions. This may be the mechanism underlying the cellular and atrophic changes of neurons previously associated with BRD1 deficiency and suggests that mitochondrial dysfunction may be a possible link between genetic variation in BRD1 and psychopathology in humans.
溴结构域蛋白 1（BRD1）编码一种表观遗传调节剂，控制与精神疾病相关的基因网络表达。BRD1 对正常大脑发育至关重要，其在遗传和临床前研究中的作用已得到证实。然而，连接其分子和神经病理学效应的神经生物学仍未得到充分探索。在这里，我们使用公开可用的数据集发现，BRD1 在细胞系中靶向核基因，这些核基因编码线粒体蛋白，并且无论 BRD1 表达是下调还是上调（下调或上调一种或另一种现有 BRD1 同工型（BRD1-L 和 BRD1-S）），都会导致这些基因的表达谱发生明显变化。我们进一步表明，在人类大脑发育过程中，核基因编码线粒体蛋白的表达与 BRD1 mRNA 的表达呈负相关。因此，我们确定了 BRD1 共转录因子中的核基因编码线粒体蛋白的关键调控因子，并提供了证据表明 BRD1 作为过氧化物酶体增殖物激活受体（PPAR）介导转录的共阻遏物发挥作用。最后，当使用定量 PCR、线粒体靶向荧光探针和 Seahorse XFe96 分析仪时，我们证明在细胞系中调节 BRD1 表达会改变线粒体生理学（mtDNA 含量和线粒体质量）、代谢（还原能力）和生物能量学（基础、最大和备用呼吸等），表现出依赖表达水平和同工型的方式。总之，我们的数据表明 BRD1 是核编码线粒体蛋白的转录调节剂，BRD1 基因组作用的中断会改变线粒体功能。这可能是先前与 BRD1 缺乏相关的神经元细胞和萎缩变化的机制，并表明线粒体功能障碍可能是 BRD1 基因变异与人类精神病理学之间的可能联系。
