Modulation of gene expression by YTH domain family (YTHDF) proteins in human physiology and pathology

The advent of high throughput techniques in the past decade has significantly advanced the field of epitranscriptomics. The internal chemical modification of the target RNA at a specific site is a basic feature of epitranscriptomics and is critical for its structural stability and functional property. More than 170 modifications at the transcriptomic level have been reported so far, among which m6A methylation is one of the more conserved internal RNA modifications, abundantly found in eukaryotic mRNAs and frequently involved in enhancing the target messenger RNA's (mRNA) stability and translation. m6A modification of mRNAs is essential for multiple physiological processes including stem cell differentiation, nervous system development and gametogenesis. Any aberration in the m6A modification can often result in a pathological condition. The deregulation of m6A methylation has already been described in inflammation, viral infection, cardiovascular diseases and cancer. The m6A modification is reversible in nature and is carried out by specialized m6A proteins including writers (m6A methyltransferases) that add methyl groups and erasers (m6A demethylases) that remove methyl groups selectively. The fate of m6A-modified mRNA is heavily reliant on the various m6A-binding proteins ("readers") which recognize and generate a functional signal from m6A-modified mRNA. In this review, we discuss the role of a family of reader proteins, "YT521-B homology domain containing family" (YTHDF) proteins, in human physiology and pathology. In addition, we critically evaluate the potential of YTHDF proteins as therapeutic targets in human diseases.