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YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 2; YTHDF2

YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 2; YTHDF2

Alternative titles; symbolsYTH DOMAIN FAMILY, MEMBER 2Other entities represented in this entry:YTHDF2/RUNX1 FUSION GENE, INCLUDEDHGNC Approved Gene Symbol: YTHDF...

Alternative titles; symbols

  • YTH DOMAIN FAMILY, MEMBER 2

Other entities represented in this entry:

  • YTHDF2/RUNX1 FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: YTHDF2

Cytogenetic location: 1p35.3 Genomic coordinates (GRCh38): 1:28,736,623-28,769,774 (from NCBI)

▼ Cloning and Expression
Nguyen et al. (2006) identified YTHDF2 as a novel RUNX1 (151385) translocation partner gene in a case of acute myeloid leukemia. The YTHDF2 breakpoint localized to the region in YTHDF2 with the highest Alu density, suggesting that Alus may have contributed to the recombination event. Nguyen et al. (2006) stated that the YTHDF2 gene encodes a 579-amino acid protein and is alternatively spliced to form 2 isoforms. Cardelli et al. (2006) noted the presence of a YTH domain in codons 457-547. A protein-translated sequence analysis revealed that the YTHDF2 protein is highly conserved in vertebrates. Using real-time PCR, Cardelli et al. (2006) observed that YTHDF2 mRNA was expressed in all 16 tissues examined, with highest expression in testis, placenta, and pancreas. Relative expression of YTHDF2 mRNA was 7- to 8-fold higher in testis than in small intestine, skeletal muscle, and heart, and 3- to 5-fold higher than in the majority of other tissues.

▼ Gene Structure
The YTHDF2 gene comprises 6 exons and is translated from exons 1 through 5 (Nguyen et al., 2006). Cardelli et al. (2006) determined that the YTHDF2 gene spans about 32 kb.

▼ Gene Function
N6-methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the mRNA of all higher eukaryotes. Wang et al. (2014) demonstrated that m6A is selectively recognized by the human YTHDF2 'reader' protein to regulate mRNA degradation. Wang et al. (2014) identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include noncoding RNAs, with a conserved core motif of G(m6A)C. Wang et al. (2014) further established the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Wang et al. (2014) concluded that their results indicated that the dynamic m6A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.

Zhou et al. (2015) showed that in response to heat shock stress, certain adenosines within the 5-prime UTR of newly transcribed mRNAs are preferentially methylated. Zhou et al. (2015) found that the dynamic 5-prime UTR methylation is a result of stress-induced nuclear localization of YTHDF2, a well-characterized m6A 'reader.' Upon heat shock stress, the nuclear YTHDF2 preserves 5-prime UTR methylation of stress-induced transcripts by limiting the m6A 'eraser' FTO (610966) from demethylation. Remarkably, the increased 5-prime UTR methylation in the form of m6A promotes cap-independent translation initiation, providing a mechanism for selective mRNA translation under heat shock stress. Using Hsp70 (140550) mRNA as an example, Zhou et al. (2015) demonstrated that a single m6A modification site in the 5-prime UTR enables translation initiation independent of the 5-prime end N(7)-methylguanosine cap. Zhou et al. (2015) concluded that their elucidation of the dynamic features of 5-prime UTR methylation and its critical role in cap-independent translation not only expands the breadth of physiologic roles of m6A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.

In human cells, Liu et al. (2015) demonstrated that m6A controls the RNA structure-dependent accessibility of RNA binding motifs to affect RNA-protein interactions for biologic regulation; they termed this mechanism 'the m6A switch.' Liu et al. (2015) found that m6A alters the local structure in mRNA and long noncoding RNA to facilitate binding of heterogeneous nuclear ribonucleoprotein C (HNRNPC; 164020). Combining photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) and anti-m6A immunoprecipitation approaches enabled Liu et al. (2015) to identify 39,060 m6A switches among HNRNPC binding sites. Global m6A reduction decreased HNRNPC binding at 2,798 high-confidence m6A switches. Liu et al. (2015) determined that these m6A switch-regulated HNRNPC binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m6A switches on gene expression and RNA maturation. Liu et al. (2015) concluded that their results illustrated how RNA binding proteins gain regulated access to their RNA binding motifs through m6A-dependent RNA structural remodeling.

Zhao et al. (2017) showed that over one-third of zebrafish maternal mRNAs can be m6A modified, and the clearance of these maternal mRNAs is facilitated by an m6A-binding protein, Ythdf2. Removal of Ythdf2 in zebrafish embryos decelerated the decay of m6A-modified maternal mRNAs and impeded zygotic genome activation. These embryos failed to initiate timely maternal-to-zygotic transition (MZT), underwent cell-cycle pause, and remained developmentally delayed throughout larval life. The study revealed m6A-dependent RNA decay as a maternally driven mechanism that regulates maternal mRNA clearance during zebrafish MZT, highlighting the critical role of m6A mRNA methylation in transcriptome switching and animal development.

Shi et al. (2017) showed that YTHDF3 (618669) interacted directly with YTHDF1 (616529) and YTHDF2 and that the proteins formed an interconnected network in the cytosol. YTHDF3 affected the binding specificities of YTHDF1 and YTHDF2 toward their target mRNAs, and all 3 YTHDFs contributed collectively to accelerating the metabolism of m6A-modified mRNAs in the cytosol. Specifically, YTHDF3 and YTHDF1 cooperatively promoted translation in an m6A-dependent manner and appeared to accelerate the subsequent decay of methylated mRNAs through a YTHDF2-mediated pathway in the cytoplasm.

Ries et al. (2019) found that the cytosolic m6A-binding proteins YTHDF1, YTHDF2, and YTHDF3 underwent liquid-liquid phase separation in vitro and in cells. This phase separation was markedly enhanced by mRNAs that contain multiple, but not single, m6A residues. Polymethylated mRNAs acted as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their low-complexity domains and thereby leading to phase separation. The resulting mRNA-YTHDF complexes then partitioned into different endogenous phase-separated compartments, such as P-bodies, stress granules, or neuronal RNA granules. m6A-mRNA is subject to compartment-specific regulation, including a reduction in the stability and translation of mRNA. Ries et al. (2019) concluded that their studies revealed that the number and distribution of m6A sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome, and suggested that the cellular properties of m6A-modified mRNAs are governed by liquid-liquid phase separation principles.

▼ Mapping
Both cytologic evidence on the location of the break in chromosome 1 and the prior evidence in silico of the location of the YTHDF2 gene agreed on the location of chromosome 1p35 (Nguyen et al., 2006).

▼ Molecular Genetics
The uneven distribution of Alu repetitive elements in the human genome is related to specific functional properties of genomic regions. Bonafe et al. (2001) identified a locus associated with human longevity (152430) in one of the chromosomal regions with the highest density of Alu elements, namely, 1p35. The locus was identified by characterizing an 'anonymous' marker detectable through inter-Alu fingerprinting, which evidenced an increased homozygosity in centenarians. Cardelli et al. (2006) determined that this locus corresponds to a (TG)n microsatellite in the fourth intron of the YTHDF2 gene. After genotyping an independent set of 412 participants of different ages, including 137 centenarians, Cardelli et al. (2006) confirmed the increased homozygosity in centenarians at this locus, and observed a concomitantly increased frequency of the most common allele and the corresponding homozygous genotype. In the whole set of samples a total of 13 different alleles was observed ranging from 199 to 229 basepairs, with all alleles differing from each other by 2 or a multiple of 2 basepairs. Direct sequencing demonstrated that the length variation was produced by the variable number of repeats in the (TG)n microsatellite, ranging from 12 to 27. A statistically significant difference (p = 0.014) emerged when the frequency of the most common alleles was compared between young participants (17 to 65 years) and centenarians. In particular, an increase of the '15' allele was observed in centenarians, with the frequency of the most common genotype (15-15) nearly doubled in centenarians compared to young participants. An odds ratio of 2.186 was achieved for the 15-15 genotype when the most abundant category (the class of less frequent genotypes) was used as the reference category. Immortalized lymphocytes with the 15-15 genotype showed a more than doubled average relative expression of YTHDF2 mRNA with respect to that observed in lymphocytes carrying other genotypes.

Tags: 1p35.3