Shi Weili, Yang Fan, Dai Ranran, Sun Yafei, Chu Yan, Liao Shixiu, Hao Bingtao
Henan Provincial People's Hospital, Medical Genetics Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, People's Hospital of Zhengzhou University, Zhengzhou, China.
National Health Commission Key Laboratory of Birth Defect Prevention, Henan Key Laboratory of Population Defects Prevention, Zhengzhou, China.
Front Cell Dev Biol. 2021 Apr 1;9:621374. doi: 10.3389/fcell.2021.621374. eCollection 2021.
Down syndrome (DS) is a common genetic condition in which a person is born with an extra copy of chromosome 21. Intellectual disability is the most common characteristic of DS. N6-methyladenosine (m6A) is a common RNA modification that is implicated in many biological processes. It is highly enriched within the brain and plays an essential role in human brain development. However, the mRNA m6A modification in the fetal brain of DS has not been explored. Here, we report m6A mRNA profiles and mRNA expression profiles of fetal brain cortex tissue from DSs and controls. We observed that the m6A modification in DS brain tissues was reduced genome-wide, which may be due to decreased the m6A methyltransferase like 3 (METTL3) protein expression. The nuclear receptor-interacting protein 1 () is coded by a highly conserved chromosome 21 (Hsa21) gene. Overexpression of NRIP1 is associated with mitochondrial dysfunction in DS. The NRIP1 mRNA increased in fetal brain tissues of DS, whereas the m6A modification of the NRIP1 mRNA significantly decreased. METTL3 knockdown reduced the m6A modification of NRIP1 mRNA and increased its expression, and an increase in NRIP1 m6A modification and a decrease in its expression were observed in METTL3-overexpressed cells. The Luciferase reporter assay confirmed that METTL3 regulates NRIP1 expression in an m6A-dependent manner. The decay rate of NRIP1 mRNA was significantly reduced in METTL3-knockdown cells but increased in METTL3-overexpressed cells. We proposed that the m6A modification of NRIP1 mRNA in DS fetal brain tissue is reduced, reducing its transcript degradation rate, resulting in abnormally increased expression of NRIP1, at least partially, in the DS brain. It provides a new mechanism for the molecular pathology of DS and leads to a new insight that may become therapeutically relevant.
唐氏综合征（DS）是一种常见的遗传疾病，患者出生时多了一条21号染色体。智力残疾是DS最常见的特征。N6-甲基腺苷（m6A）是一种常见的RNA修饰，参与许多生物学过程。它在大脑中高度富集，对人类大脑发育起着至关重要的作用。然而，DS胎儿大脑中的mRNA m6A修饰尚未被研究。在此，我们报告了DS患者和对照组胎儿脑皮质组织的m6A mRNA图谱和mRNA表达图谱。我们观察到DS脑组织中的m6A修饰在全基因组范围内减少，这可能是由于m6A甲基转移酶样3（METTL3）蛋白表达降低所致。核受体相互作用蛋白1（NRIP1）由高度保守的21号染色体（Hsa21）基因编码。NRIP1的过表达与DS中的线粒体功能障碍有关。DS胎儿脑组织中NRIP1 mRNA增加，而NRIP1 mRNA的m6A修饰显著减少。METTL3敲低降低了NRIP1 mRNA的m6A修饰并增加了其表达，在METTL3过表达的细胞中观察到NRIP1 m6A修饰增加而其表达减少。荧光素酶报告基因检测证实METTL3以m6A依赖的方式调节NRIP1的表达。在METTL3敲低的细胞中，NRIP1 mRNA的降解速率显著降低，但在METTL3过表达的细胞中增加。我们提出，DS胎儿脑组织中NRIP1 mRNA的m6A修饰减少，降低了其转录本降解速率，导致DS大脑中NRIP1表达异常增加，至少部分如此。它为DS的分子病理学提供了一种新机制，并带来了可能具有治疗意义的新见解。
