Mettl14-driven senescence-associated secretory phenotype facilitates somatic cell reprogramming

Area of Science:

• Epigenetics and Stem Cell Biology
• Cellular Reprogramming Mechanisms
• Senescence and Inflammation

Background:

• The METTL3-METTL14 complex is a key regulator of N⁶-methyladenosine (m⁶A) modification.
• Mettl3 overexpression promotes somatic cell reprogramming by increasing m⁶A levels.
• The role of Mettl14 in cellular reprogramming remains less understood.

Purpose of the Study:

• To investigate the function of Mettl14 in induced pluripotent stem cell (iPSC) generation.
• To determine whether Mettl14's effect on reprogramming is dependent on m⁶A.
• To elucidate the molecular mechanisms underlying Mettl14-mediated reprogramming.

Main Methods:

• Overexpression of Mettl14 in somatic cells during reprogramming.
• Analysis of m⁶A levels and gene expression.
• Assessment of senescence-associated secretory phenotype (SASP) markers, including interleukin-6 (IL-6).
• Pharmacological inhibition of SASP using senolytic agents and NF-κB inhibitors.

Main Results:

• Mettl14 significantly enhances iPSC generation in an m⁶A-independent manner.
• Overexpressed Mettl14 transiently promotes SASP gene expression, including IL-6, in late-stage reprogramming.
• IL-6 is identified as a key mediator of Mettl14's pro-reprogramming effect.
• Blocking SASP or IL-6 signaling impairs Mettl14-enhanced reprogramming.

Conclusions:

• Mettl14 possesses a critical m⁶A-independent function in promoting somatic cell reprogramming.
• The senescence-associated secretory phenotype, particularly IL-6, plays a vital role in Mettl14-mediated reprogramming.
• This study reveals a novel link between senescence pathways and epigenetic reprogramming, offering new therapeutic targets.