METTLing in Stem Cell and Cancer Biology

Abstract

The methyltransferase-like (METTL) family is a diverse group of methyltransferases that can methylate nucleotides, proteins, and small molecules. Despite this diverse array of substrates, they all share a characteristic seven-beta-strand catalytic domain, and recent evidence suggests many also share an important role in stem cell biology. The most well characterized family members METTL3 and METTL14 dimerize to form an N⁶-methyladenosine (m⁶A) RNA methyltransferase with established roles in cancer progression. However, new mouse models indicate that METTL3/METTL14 are also important for embryonic stem cell (ESC) development and postnatal hematopoietic and neural stem cell self-renewal and differentiation. METTL1, METTL5, METTL6, METTL8, and METTL17 also have recently identified roles in ESC pluripotency and differentiation, while METTL11A/11B, METTL4, METTL7A, and METTL22 have been shown to play roles in neural, mesenchymal, bone, and hematopoietic stem cell development, respectively. Additionally, a variety of other METTL family members are translational regulators, a role that could place them as important players in the transition from stem cell quiescence to differentiation. Here we will summarize what is known about the role of METTL proteins in stem cell differentiation and highlight the connection between their growing importance in development and their established roles in oncogenesis.

Keywords: Cancer; METTL; Metabolism; Methyltransferase; Stem cell; Transcription; Translation.

Fig. 1. Evolutionary analysis of the METTL family by Maximum Likelihood method:

The evolutionary history was inferred by using the maximum likelihood method and Le/Gascuel model (179). The tree with the highest log likelihood (−14505.17) is shown. Initial tree(s) for the heuristic search were obtained automatically by applying Neighbor-Join and BioNJ algorithms to a matrix of pairwise distances estimated using the JTT model, and then selecting the topology with superior log likelihood value. The tree is drawn to scale, with branch lengths measured in the number of substitutions per site. This analysis involved 33 amino acid sequences. All positions with less than 90% coverage were eliminated, i.e., fewer than 10% alignment gaps, missing data, and ambiguous bases were allowed at any position (partial deletion option). There were a total of 175 positions in the final dataset. Evolutionary analyses were conducted in MEGA X (180).

Fig. 2. Summary of known oncogenic and stem cell developmental roles of METTL family members:

(A) To date, the majority of METTL proteins exhibit oncogenic activity, with few acting as both oncogenes and tumor suppressors, and none exhibiting only tumor suppressor activity. (B) There is a more even divide when it comes to stem cell development, with the majority promoting differentiation or playing dual roles in the maintenance of pluripotency and transition to a differentiated state.

Fig. 3. Mechanisms shared by cancer and stem cells to exit quiescence and begin proliferation:

To re-enter the cell cycle both cancer and stem cells have to alter their transcriptional programs, activate metabolism, and increase protein translation. METTL family members play roles in all three of these processes, and some have overlapping roles in more than one. These roles are substrate-specific and are likely to expand as additional METTL family targets are identified.