METTL3 regulates heterochromatin in mouse embryonic stem cells

Area of Science:

• Epigenetics and Gene Regulation
• RNA Biology
• Mammalian Development

Background:

• Methyltransferase-like 3 (METTL3) is known to methylate mRNA at the N6-methyladenosine (m6A) site, influencing mRNA stability and translation.
• METTL3's role in chromatin binding and its impact on heterochromatin, particularly concerning endogenous retroviruses, remains incompletely understood.

Purpose of the Study:

• To investigate the function of METTL3 and m6A methylation in regulating heterochromatin integrity in mouse embryonic stem cells.
• To elucidate the mechanism by which METTL3 controls endogenous retroviral elements within the genome.

Main Methods:

• Analysis of METTL3 localization and function in mouse embryonic stem cells, focusing on intracisternal A particle (IAP) retroviruses.
• Investigation of heterochromatin mark deposition, retroviral transcription, and the interaction of METTL3 with RNA transcripts and chromatin-modifying proteins (SETDB1, TRIM28).
• Utilized m6A reader YTHDC1 to study its interaction with METTL3 and chromatin association.

Main Results:

• METTL3 knockout impaired heterochromatin formation on IAPs and increased IAP transcription, indicating METTL3's role in IAP heterochromatin integrity.
• METTL3-bound IAP transcripts are m6A-methylated, interact with YTHDC1, and promote METTL3's chromatin association.
• METTL3 physically interacts with SETDB1 and TRIM28, facilitating their localization to IAPs.

Conclusions:

• METTL3-catalyzed m6A RNA modification is essential for maintaining IAP heterochromatin integrity in mouse embryonic stem cells.
• This study reveals a novel mechanism of heterochromatin regulation in mammals involving METTL3 and RNA methylation.