MiR-421 Binds to PINK1 and Enhances Neural Stem Cell Self-Renewal via HDAC3-Dependent FOXO3 Activation

Abstract

Dysfunctions of neural stem cells (NSCs) often lead to a variety of neurological diseases. Thus, therapies based on NSCs have gained increasing attention recently. It has been documented that microRNA (miR)-421 represses the autophagy and apoptosis of mouse hippocampal neurons and confers a role in the repair of ischemic brain injury (IBI). Herein, we aimed to illustrate the effects of miR-421 on NSC self-renewal. The downstream factors of miR-421 were predicted initially, followed by gain- and loss-of-function assays to examine their effects on NSC self-renewal. Immunoprecipitation and dual luciferase assays were conducted to validate the interaction among miR-421, PTEN-induced putative kinase 1 (PINK1), HDAC3, and forkhead box O3 (FOXO3). A mouse model with IBI was developed to substantiate the impact of the miR-421/PINK1/HDAC3/FOXO3 axis on NSC self-renewal. The expression of miR-421 was downregulated during differentiation of human embryonic NSCs, and miR-421 overexpression accelerated NSC self-renewal. Besides, miR-421 targeted PINK1 and restricted its expression in NSCs and further suppressed HDAC3 phosphorylation and enhanced FOXO3 acetylation. In conclusion, our data elucidated that miR-421 overexpression may facilitate NSC self-renewal through the PINK1/HDAC3/FOXO3 axis, which may provide potential therapeutic targets for the development of novel therapies for IBI.

Expression and Regulation Network of HDAC3 in Acute Myeloid Leukemia and the Implication for Targeted Therapy Based on Multidataset Data Mining

“…HDAC can remove acetyl groups from the amino terminus of lysine residues on histones, while histone acetyltransferases (HATS) promote the addition of lysine residues, leading to structural changes in local chromatin [8,[39][40][41], which is an important step in regulating protein entry into DNA [7]. Studies have shown that HDAC and HATS enzymes are involved in the regulation of transcription Computational and Mathematical in Medicine factors, transcription modulators, and DNA repair proteins [42].…”

“…Histone deacetylase (HDAC) is a kind of regulation of histone acetylation by protease, the enzyme can be removed from lysine acetyl, and most of the work, by protein complexes formed, is the modification of the chromosome structure and gene expression regulation and control important regulatory factors [ 7 , 8 ]. Conversely, deacetylation can also lead to transcriptional inhibition and impaired hematopoietic differentiation.…”

Phosphatase and Tensin Homology Deleted on Chromosome 10 Inhibitors Promote Neural Stem Cell Proliferation and Differentiation

“…mTOR is an important signaling molecule in the PTEN signaling pathway, which regulates pentameric neuronal ASH2-like, histone lysine methyltransferase complex subunit at the transcriptional level ( Nguyen and Anderson, 2018 ). Consequently, it affects neuronal differentiation and directional axonal outgrowth ( Jia et al, 2021 ). PI3K/AKT/mTOR signaling was shown to regulate neuronal cell maturation and differentiation, while Park ( Park et al, 2008 ) reported regeneration of the optic nerve after PTEN knockdown following the reactivation of PI3K/Akt/mTOR signaling.…”