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Updated: Aug 3, 2025

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METTL14 is a chromatin regulator independent of its RNA N6-methyladenosine methyltransferase activity

Xiaoyang Dou1,2, Lulu Huang3, Yu Xiao1,2

  • 1Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.

Protein & Cell
|April 8, 2023
PubMed

Insights

METTL14 regulates gene expression independently of RNA m6A modification by interacting with H3K27me3. This novel mechanism is crucial for mouse embryonic stem cell differentiation and self-renewal.

Area of Science:

  • Epigenetics and Gene Regulation
  • Stem Cell Biology
  • RNA Biology

Background:

  • The methyltransferase-like 3 (METTL3) and METTL14) complex is the primary writer of RNA N6-adenosine methylation (m6A).
  • Distinct roles of METTL3 and METTL14 in maintaining mouse embryonic stem cell (mESC) stemness were observed, despite similar global m6A hypomethylation upon knockout.

Purpose of the Study:

  • To elucidate the distinct functions of METTL14 beyond its role in m6A methylation.
  • To investigate the m6A-independent regulatory mechanisms of METTL14 in mESCs.

Main Methods:

  • Comparative analysis of Mettl3 and Mettl14 knockout mESCs.
  • Assessment of nascent RNA synthesis and global gene expression.
  • Chromatin immunoprecipitation and colocalization studies with H3K27me3.
  • Investigation of KDM6B recruitment and H3K27me3 demethylation.

Main Results:

  • METTL14 depletion caused decreased nascent RNA synthesis and global gene suppression, unlike METTL3 depletion which upregulated transcription.
  • METTL14, but not METTL3, was found to colocalize with and bind to H3K27me3.
  • METTL14 recruits KDM6B to demethylate H3K27me3 in an m6A-independent manner.
  • Depletion of METTL14 led to increased H3K27me3 levels and global gene silencing.

Conclusions:

  • METTL14 possesses an m6A-independent function in gene regulation by modulating H3K27me3 levels.
  • This heterochromatin regulatory mechanism is essential for mESC self-renewal and differentiation.
  • METTL14's distinct role impacts transcriptional regulation and stem cell fate decisions.
Keywords:
H3K27me3METTL14chromatinm6A-independentmESC differentiation

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