Recent studies reported here at Epigenie have identified N6-methyladenosine (m6A) as a highly dynamic RNA modification that influences all aspects of RNA biology. Furthermore, an interesting study in mouse and human embryonic stem cells (ESCs) has indicated a role for N6-methyladenosine in the switch between ESC pluripotency and differentiation. Cool stuff indeed, but whate regulates N6-methyladenosine deposition on mRNA remains unknown.
Now, new research from Francesca Aguilo and Martin J Walsh has delineated the importance of the N6-methyladenosine modification to pluripotency and how pluripotent stem cells bridge epigenetic and epitranscriptomic networks.
They initially found that the expression of the Zfp217 transcription factor enhanced mRNA transcription of pluripotency-associated genes, but they also found that Zfp217 inhibited N6-methyladenosine modification of the same mRNAs. Low N6-methyladenosine levels are known to inhibit mRNA degradation, so this promoted the pluripotent state of mouse ESCs.
The researchers discovered that Zfp217 achieves this dual function by interacting with epigenetic modifiers and binding the regulatory regions of pluripotency-associated genes to enhance mRNA transcription, and at the same time, Zfp217 sequesters m6A methyltransferase-like 3 (Mettl3) away from its core partner Mettl14, thereby inhibiting the deposition of N6-methyladenosine on mRNA. Therefore, Zfp217 boosts mRNA transcription and inhibits mRNA degradation at the same time to maintain pluripotency. To confirm this, the authors inhibited Zfp217 expression using short hairpin RNAs and found that N6-methyladenosine levels on pluripotency-associated mRNAs increased, their degradation rates increased, and ESCs lost their pluripotent characteristics and differentiated.
Zfp217 seems to bring all a pluripotent cell needs: the epigenetic power and pizzazz to set-off the pluripotent mRNA transcription, and post-transcriptional care and stability required to look after the produced mRNA. But does this regulatory mechanism function in human pluripotent cell types? The authors point to studies into the human Zfp217 homolog (ZNF217) which show that tumor cells overexpressing ZNF217 can proliferate freely and fail to differentiate, so suggesting a firm link to self-renewal/pluripotency.
Get the low down on this interesting new regulatory mechanism at Cell Stem Cell, December 2015.