The study investigates the role of the N6-adenosine methyltransferase METTL16 in regulating the expression of the human MAT2A gene, which encodes the SAM synthetase. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhancing the splicing of a retained intron. This induction requires METTL16 and its methylation substrate, a vertebrate-conserved hairpin (hp1) in the MAT2A 3′ UTR. Increasing METTL16 occupancy on the MAT2A 3′ UTR is sufficient to induce efficient splicing. The authors propose that under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, promoting MAT2A splicing. They also show that METTL16 is the long-unknown methyltransferase for the U6 snRNA, suggesting that this enzyme evolved an additional function in vertebrates to regulate SAM homeostasis. The study provides insights into the regulation of SAM levels and the role of METTL16 in mRNA and snRNA methylation.The study investigates the role of the N6-adenosine methyltransferase METTL16 in regulating the expression of the human MAT2A gene, which encodes the SAM synthetase. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhancing the splicing of a retained intron. This induction requires METTL16 and its methylation substrate, a vertebrate-conserved hairpin (hp1) in the MAT2A 3′ UTR. Increasing METTL16 occupancy on the MAT2A 3′ UTR is sufficient to induce efficient splicing. The authors propose that under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, promoting MAT2A splicing. They also show that METTL16 is the long-unknown methyltransferase for the U6 snRNA, suggesting that this enzyme evolved an additional function in vertebrates to regulate SAM homeostasis. The study provides insights into the regulation of SAM levels and the role of METTL16 in mRNA and snRNA methylation.