2. Academic Validation
  3. DNMT3L promotes neural differentiation by enhancing STAT1 and STAT3 phosphorylation independent of DNA methylation

DNMT3L promotes neural differentiation by enhancing STAT1 and STAT3 phosphorylation independent of DNA methylation

  • Prog Neurobiol. 2021 Jun;201:102028. doi: 10.1016/j.pneurobio.2021.102028.
Lin Qin 1,  Chong Qiao 2,  Volney Sheen 3,  Yu Wang 4,  Jie Lu 5
Affiliations

Affiliations

  • 1 Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, 110122, China; Department of Obstetrics & Gynecology, Shenyang Women & Children's Hospital, Shenyang, Liaoning Province, 110121, China. Electronic address: echo19830129@hotmail.com.
  • 2 Department of Obstetrics & Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China. Electronic address: qiaochong2002@hotmail.com.
  • 3 Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. Electronic address: vsheen@bidmc.harvard.edu.
  • 4 Department of Obstetrics & Gynecology, Shenyang Women & Children's Hospital, Shenyang, Liaoning Province, 110121, China. Electronic address: wang_yu007@sohu.com.
  • 5 Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, 110122, China. Electronic address: lvjie@cum.edu.cn.
PMID: 33636226 DOI: 10.1016/j.pneurobio.2021.102028
Abstract

Previously, we reported global hypermethylation in DS might be attributed to the overexpression of HSA21 gene DNMT3L, which can enhance DNMT3A and DNMT3B activities in DNA methylation. To test this hypothesis, we compared the DNA methylation and RNA expression profiles of early-differentiated human neuroprogenitors with and without DNMT3L overexpression. We found DNMT3L overexpression only moderately increased the DNA methylation of limited genes, yet significantly altered global RNA expression of genes involved in neural differentiation. We further found that DNMT3L bound STAT1 or STAT3, and increased its phosphorylation and nuclear translocation, which in turn activated the expression of transcription factors including HES3, ASCL1, NEUROD2 and NEUROG2 and CDK Inhibitor CDKN1A, which promoted cell cycle exit and neural differentiation. This phenomenon was also confirmed in Dnmt3l conditional knockin mice, which could be rescued by STAT1 and STAT3 phosphorylation inhibitors (Fludarabine and SH-4-54) but not DNA methylation inhibitor (Decitabine). These results suggest that DNMT3L play an important role during neurodevelopment independent of DNA methylation, which may contribute to the abnormal phenotypes observed in Down syndrome cortex.

Keywords

DNA methylation; DNMT3L; Differentiation; Neurogenesis; STAT1; STAT3.

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