m⁶A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during...

Area of Science:

• Molecular Biology
• Immunology
• Developmental Biology

Background:

• N6-methyladenosine (m6A) is the most prevalent epitranscriptomic modification in eukaryotic mRNA.
• The precise functions of m6A during mammalian development, particularly in hematopoiesis, remain largely unelucidated.
• METTL3 is a key methyltransferase responsible for catalyzing m6A formation.

Purpose of the Study:

• To investigate the role of METTL3-mediated m6A modification in mammalian hematopoietic development.
• To determine the molecular mechanisms underlying hematopoietic defects in the absence of METTL3.
• To explore the potential link between m6A modification and innate immune responses during hematopoiesis.

Main Methods:

• Conditional knockout of METTL3 in murine fetal liver hematopoietic stem cells.
• Analysis of hematopoietic progenitor cell function in vitro and in vivo.
• Detection and characterization of endogenous double-stranded RNAs (dsRNAs).
• Assessment of pattern recognition receptor (PRR) pathway activation and downstream signaling.

Main Results:

• Conditional deletion of METTL3 led to severe hematopoietic failure and perinatal lethality in mice.
• Loss of METTL3 resulted in the accumulation of aberrant, long, and highly m6A-modified endogenous dsRNAs.
• Aberrant dsRNA formation triggered innate immune responses via pattern recognition receptor pathways (e.g., MAVS, RNaseL).
• Partial rescue of hematopoietic defects was observed upon abrogation of MAVS or RNaseL signaling.

Conclusions:

• m6A modification, catalyzed by METTL3, is essential for preventing the formation of deleterious endogenous dsRNAs during mammalian hematopoietic development.
• METTL3-dependent m6A modification acts as a critical safeguard against aberrant innate immune activation in the hematopoietic system.
• Targeting m6A pathways or downstream immune signaling could offer therapeutic strategies for hematopoietic disorders.