Mettl3-catalyzed m⁶A regulates histone modifier and modification expression in self-renewing somatic tissue

Area of Science:

• Molecular Biology
• Developmental Biology
• Epigenetics

Background:

• N6-methyladenosine (m6A) is the most prevalent mRNA modification.
• Methyltransferase-like protein 3 (Mettl3) catalyzes m6A formation.
• The role of m6A in self-renewing somatic tissues is not fully understood.

Purpose of the Study:

• To investigate the function of m6A and Mettl3 in epidermal progenitors.
• To elucidate the mechanisms by which m6A regulates epithelial development and self-renewal.

Main Methods:

• In vivo deletion of Mettl3 in mouse epidermal progenitors.
• Analysis of phenotypic abnormalities, including hair follicle morphogenesis, cell adhesion, and polarity.
• Assessment of mRNA degradation, m6A modification levels, and gene expression of histone modifying enzymes.

Main Results:

• Mice lacking Mettl3 exhibited impaired hair follicle development, cell adhesion, and polarity.
• Mettl3 depletion led to increased expression of mRNAs encoding histone modifying enzymes.
• Loss of m6A on these target mRNAs resulted in widespread gene expression abnormalities.

Conclusions:

• Mettl3-catalyzed m6A is crucial for proper epithelial development and self-renewal.
• Mettl3 regulates the degradation of specific mRNAs, including those encoding chromatin modifiers.
• m6A represents a key regulatory layer in epithelial gene expression and tissue homeostasis.