Mechanism of METTL3-mediated m6A modification in depression-induced cognitive deficits

IF 1.6 3区 医学 Q3 GENETICS & HEREDITY
Juan Niu, Bailing Wang, Tian Wang, Tiantian Zhou
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引用次数: 7

Abstract

Depressive disorder (DD) is associated with N6-methyladenosine (m6A) hypermethylation. This study sought to explore the molecular mechanism of Methyltransferase-like 3 (METTL3) in cognitive deficits of chronic unpredictable mild stress (CUMS)-treated rats and provide novel targets for DD treatment. A DD rat model was established via CUMS treatment. Cognitive deficits were assessed via body weighing and behavioral tests. METTL3, microRNA (miR)-221-3p, pri-miR-221, GRB2-associated binding protein 1 (Gab1) expressions in hippocampal tissues were detected via RT-qPCR and Western blotting. m6A, DiGeorge syndrome critical region gene 8 (DGCR8)-bound pri-miR-221 and pri-miR-221 m6A levels were measured. The binding relationship between miR-221-3p and Gab1 was testified by dual-luciferase and RNA pull-down assays. Rescue experiments were designed to confirm the role of miR-221-3p and Gab1. METTL3 was highly expressed in CUMS rats, and silencing METTL3 attenuated cognitive deficits of CUMS rats. METTL3-mediated m6A modification facilitated processing and maturation of pri-miR-221 via DGCR8 to upregulate miR-221-3p. miR-221-3p targeted Gab1. miR-221-3p overexpression or Gab1 downregulation reversed the role of silencing METTL3 in CUMS rats. Overall, METTL3-mediated m6A modification facilitated processing and maturation of pri-miR-221 to upregulate miR-221-3p and then inhibit Gab1, thereby aggravating cognitive deficits of CUMS rats.

mettl3介导的m6A修饰在抑郁症认知缺陷中的作用机制
抑郁症(DD)与n6 -甲基腺苷(m6A)高甲基化有关。本研究旨在探索甲基转移酶样3 (METTL3)在慢性不可预测轻度应激(CUMS)治疗大鼠认知缺陷中的分子机制,并为DD治疗提供新的靶点。经CUMS治疗建立DD大鼠模型。通过体重和行为测试评估认知缺陷。采用RT-qPCR和Western blotting检测海马组织中METTL3、microRNA (miR)-221-3p、pri-miR-221、grb2相关结合蛋白1 (Gab1)的表达。测定DGCR8结合的pri-miR-221和pri-miR-221 m6A水平。通过双荧光素酶和RNA下拉实验证实了miR-221-3p与Gab1的结合关系。设计救援实验以确认miR-221-3p和Gab1的作用。METTL3在CUMS大鼠中高表达,沉默METTL3可减轻CUMS大鼠的认知缺陷。mettl3介导的m6A修饰通过DGCR8促进pri-miR-221的加工和成熟,从而上调miR-221-3p。miR-221-3p靶向Gab1。在CUMS大鼠中,miR-221-3p过表达或Gab1下调可逆转沉默METTL3的作用。总的来说,mettl3介导的m6A修饰促进了pri-miR-221的加工和成熟,从而上调miR-221-3p,进而抑制Gab1,从而加重了CUMS大鼠的认知缺陷。
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来源期刊
CiteScore
5.90
自引率
7.10%
发文量
40
审稿时长
4-8 weeks
期刊介绍: Neuropsychiatric Genetics, Part B of the American Journal of Medical Genetics (AJMG) , provides a forum for experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. It is a resource for novel genetics studies of the heritable nature of psychiatric and other nervous system disorders, characterized at the molecular, cellular or behavior levels. Neuropsychiatric Genetics publishes eight times per year.
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