While the single transcripts from the X chromosome may have a tough time competing with the one-two combination from their autosomal counterparts, heavy-hitting new findings now demonstrate that the m6A RNA modification lends a hand and levels the RNA stability playing field.
The N6-methyladenosine RNA modification (m6A) recruits YTHDF proteins to reduce modified RNA stability by promoting their degradation, and now, rough-and-tumble researchers headed by the always equitable Julian König (Institute of Molecular Biology, Mainz, Germany) report that this modification contributes to the regulation of X-to-autosome dosage compensation by leveling the playing field in this RNA stability face-off.
Let’s hear about the fight for equality between the X chromosome and autosomes from Rücklé, Körtel, and colleagues:
- SLAM-seq assays capture significantly longer half-lives of X-chromosomal transcripts compared to autosomal transcripts in male mouse embryonic stem cells (mESCs)
- SLAM-seq and RNA-seq reveal that inhibition of the methyltransferase Mettl3 with the small-molecule STM2457 prompts acute m6A depletion and significantly increases the half-lives of autosomal transcripts but not X-chromosomal transcripts
- Comparable results in male human fibroblasts highlight a conserved role for m6A in X-to-autosome dosage compensation in mammals
- Analysis of distribution across chromosomes in mESCs, mouse heart samples (female), and macrophages (male) via miCLIP2 data reveal fewer m6A modifications on X-chromosomal transcripts than autosomal transcripts
- m6A generally appears in a DRACH consensus sequence; where reduced levels of m6A on X-chromosomal transcripts derive from a lower frequency of the GGACH motif (the most frequently methylated DRACH motif) on the X chromosome
- RNA-seq experiments involving
- Mettl3 inhibition indicate that m6A-dependent destabilization of autosomal transcripts also occurs in female mESCs prior to X chromosome inactivation
- These findings support the intrinsic encoding of reduced m6A levels in GGACH motif content
Overall, these findings describe how low m&a levels play a role in the higher stability of X-chromosomal transcripts, thereby providing evidence for an epitranscriptomic contribution to mammalian dosage compensation. Future research aims include exploring how hardcoded m6A-mediated dosage compensation evolved and how dosage compensation becomes globally modulated in different tissues, developmental stages, and pathological conditions.
For more on how RNA modifications can level the playing field in this X-to-autosome face-off, see Nature Structural & Molecular Biology, May 2023.