Messenger RNA (mRNA) is the transportable molecule that takes a copy of the genetic information from the DNA in the nucleus into the cytoplasm of the cell to be translated into protein. mRNA can be chemically modified by methylation on adenosine bases by an enzyme called METTL3 (methyltransferase-like 3). This so-called m6A methylation is known to affect cellular processes involving mRNA such as mRNA stability and protein translation. Intriguingly, METTL3 has also been detected in the nucleus binding to chromatin, the complex of DNA and proteins. However, it is not clear what role METTL3 and m6A methylation play in chromatin.
Ludwig Oxford’s Professor Yang Shi and collaborators at Fudan University have investigated this question in a mouse embryonic stem cell model and the results have recently been published in the journal Nature. The researchers found that METTL3 and m6A play an important role in a type of chromatin called heterochromatin. Heterochromatin is a more densely packaged DNA-protein structure with reduced accessibility to the DNA that represses the expression of genes and other DNA elements. Most of the mammalian genome consists of non-coding DNA that contains repetitive regions and relics of old viral infections, including regions called intracisternal A particles (IAPs). To maintain the integrity of the genome and for proper development, it is important that this DNA is effectively silenced by the heterochromatin structure.
This new research has uncovered the importance of METTL3 in maintaining heterochromatin at IAPs. METTL3 was found to localise to IAPs and is required for key repressive chemical modifications to the chromatin in these regions.
Looking into this discovery in more detail, the researchers found that RNA produced from IAPs associates with chromatin and is m6A methylated by METTL3. This chromatin-associated methylated RNA is bound by a protein called YTHDC1, which, in a self-reinforcing loop, can interact with METTL3 and recruit more METTL3 to chromatin. Chromatin-associated METTL3 interacts with an enzyme called SETDB1 and its co-factor TRIM28 that deposits one of the key repressive heterochromatin chemical modifications.
Therefore, METTL3 has an important function in maintaining IAP heterochromatin, not only by recruiting key repressive factors to IAPs through physical interactions but also by reinforcing repression through its methylation of IAP RNAs. These multiple levels of positive feedback help to maintain heterochromatin at IAPs to ensure genome integrity.