Project Details
Projekt
The epitranscriptome (m6A, m1A and Nm) in regulation of RNA fate
Subject Area
Developmental Biology
Term
from 2018 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 390709397
Reversible epigenetic modifications regulate gene expression to define cell fate and response to environmental stimuli. Gene expression tuning by DNA and chromatin modifications is well studied, yet the effect of RNA modifications on gene expression is only starting to be revealed. More than a hundred chemical modifications decorate RNAs, mainly non-coding ones, expanding their nucleotide vocabulary and mediating their diverse functions. Only recently were several modifications globally mapped in mRNA by members of this consortium. N6-methyladenosine (m6A) was the first modification whose topology, mainly localization around the stop codon, was determined by high-throughput methods. In the few years that elapsed since, its "writers", "erasers" and "readers" were discovered, enabling the deciphering of the functional roles of this modification in splicing, RNA decay, localization and translation. A few months ago, groups in this consortium identified another epitranscriptome mark, N1-methyladeonsine (m1A) that decorates thousands of transcript preferentially in the vicinity of the start codon. Our preliminary results indicate that m1A dynamically responds to environmental stimuli and plays a central role in translation regulation. Our preliminary results, based on a new mapping technology, identified a third type of mRNA methylation, 2'-O-methylation (Nm) on the ribose, that tends to appear near internal splice sites and to concentrate in codons of only three amino acids. This proposal brings together six groups with expertise and achievements in RNA biology and bioinformatics, and aims at discovering the function and regulatory mechanisms of these new RNA modifications, acting individually and in concert to control RNA fate. We plan to improve the mapping methodologies, to tailor bioinformatic tools for their analysis and to identify the key machineries responsible for their installation, removal and binding. Manipulation of the components that will be discovered will be performed in two model systems, mammalian and Drosophila, that proved instrumental in the pioneering studies of m6A functions. The new field of RNA modifications, now termed epitranscriptomics, has made major strides to the central stage of gene expression control. The suggested cooperative study has the potential to expand the vocabulary of RNA epigenetic modifications and to promote our understanding of the multi-layered regulation of gene expression, relevant to normal development, homeostasis and disease.
DFG Programme
DIP Programme
International Connection
Israel
