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YTHDF2/3 Are Required for Somatic Reprogramming through Different RNA Deadenylation Pathways.

Jiadong Liu1, Mingwei Gao1, Shuyang Xu2

  • 1CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.

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|September 9, 2020
PubMed
Summary
This summary is machine-generated.

YTHDF2 and YTHDF3 proteins are crucial for reprogramming somatic cells into induced pluripotent stem cells (iPSCs) by clearing somatic gene messenger RNAs. Their absence hinders this process, impacting cell fate.

Keywords:
Hippo signaling pathwayRNA degradationYTHDFsreprogramming

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Area of Science:

  • Epigenetics
  • RNA biology
  • Stem cell biology

Background:

  • N6-methyladenosine (m6A) is the most abundant reversible modification on eukaryotic messenger RNA.
  • YT521-B homology domain (YTHDF) proteins are key readers of m6A modifications, regulating gene expression.
  • Induced pluripotent stem cells (iPSCs) are generated by reprogramming somatic cells, a process involving complex molecular changes.

Purpose of the Study:

  • To investigate the role of YTHDF proteins in somatic cell reprogramming into iPSCs.
  • To elucidate the molecular mechanisms by which YTHDF proteins regulate this reprogramming process.

Main Methods:

  • CRISPR-Cas9 gene editing to generate Ythdf2/3-deficient cells.
  • RNA sequencing to analyze gene expression changes.
  • Biochemical assays to study protein-complex interactions.
  • Functional assays to assess reprogramming efficiency.

Main Results:

  • YTHDF2 and YTHDF3, but not YTHDF1, are essential for efficient iPSC reprogramming.
  • YTHDF3 recruits the PAN2-PAN3 deadenylase complex, promoting mRNA clearance of somatic genes like Tead2 and Tgfb1.
  • YTHDF2/3 deficiency impairs mesenchymal-to-epithelial transition (MET) and chromatin silencing.
  • Depletion of Tgfb1 or Hippo pathway components rescues reprogramming defects in Ythdf2/3-deficient cells.

Conclusions:

  • YTHDF2/3 proteins are critical regulators of iPSC reprogramming by coupling RNA deadenylation with the clearance of somatic genes.
  • These findings provide novel insights into the posttranscriptional regulation of cell reprogramming.