YTHDF2

Description

The YTHDF2 (YTH N6-methyladenosine RNA binding protein F2) is a protein-coding gene located on chromosome 1.

YTH N6-methyladenosine RNA binding protein 2 is a protein that in humans is encoded by the YTHDF2 gene. This gene encodes a member of the YTH (YT521-B homology) superfamily containing YTH domain. The YTH domain is typical for the eukaryotes and is particularly abundant in plants. The YTH domain is usually located in the middle of the protein sequence and may function in binding to RNA. In addition to a YTH domain, this protein has a proline-rich region which may be involved in signal transduction. An Alu-rich domain has been identified in one of the introns of this gene, which is thought to be associated with human longevity. Also, reciprocal translocations between this gene and the Runx1 (AML1) gene on chromosome 21 has been observed in patients with acute myeloid leukemia. This gene was initially mapped to chromosome 14, which was later turned out to be a pseudogene. Alternatively, spliced transcript variants encoding different isoforms have been identified in this gene. [provided by RefSeq, Oct 2012].

YTHDF2 specifically recognizes and binds to N6-methyladenosine (m6A) modified RNA molecules, playing a crucial role in regulating their stability. m6A is a chemical modification found within mRNA and some non-coding RNAs, influencing mRNA stability and processing. YTHDF2 acts as a regulator of mRNA stability by promoting the degradation of m6A-containing mRNAs through interactions with the CCR4-NOT and ribonuclease P/MRP complexes, depending on the cellular context. YTHDF2, alongside its paralogs YTHDF1 and YTHDF3, share m6A-containing mRNA targets and collectively mediate mRNA degradation and cellular differentiation. m6A-containing mRNAs that possess a binding site for RIDA/HRSP12 (5'-GGUUC-3') undergo preferential degradation via endoribonucleolytic cleavage. This occurs due to the cooperative binding of RIDA/HRSP12 and YTHDF2 to transcripts, leading to the recruitment of the ribonuclease P/MRP complex. Alternatively, other m6A-containing mRNAs undergo deadenylation through a direct interaction between YTHDF2 and CNOT1, recruiting the CCR4-NOT complex and subsequently deadenylating the m6A-containing mRNAs. YTHDF2 is maternally required to regulate oocyte maturation, likely by binding to m6A-containing mRNAs, thereby controlling maternal transcript dosage during oocyte maturation, which is essential for oocyte competence in sustaining early zygotic development. Additionally, it plays a role during spermatogenesis by regulating spermagonial adhesion through the promotion of degradation of m6A-containing transcripts encoding matrix metallopeptidases. YTHDF2 is involved in hematopoietic stem cell specification by binding to m6A-containing mRNAs, promoting their degradation. It also acts as a regulator of neural development by promoting m6A-dependent degradation of neural development-related mRNA targets. YTHDF2 inhibits neural specification of induced pluripotent stem cells by binding to methylated neural-specific mRNAs and promoting their degradation, thus restraining neural differentiation. It further regulates circadian regulation of hepatic lipid metabolism by promoting m6A-dependent degradation of PPARA transcripts. YTHDF2 regulates the innate immune response to infection by inhibiting the type I interferon response through binding to m6A-containing IFNB transcripts and promoting their degradation. It might also act as a promoter of cap-independent mRNA translation following heat shock stress. Upon stress, YTHDF2 relocalizes to the nucleus and specifically binds mRNAs with m6A methylation marks at their 5'-UTR, protecting these mRNAs from demethylation by FTO, thereby promoting cap-independent mRNA translation. YTHDF2 regulates mitotic entry by promoting the phase-specific m6A-dependent degradation of WEE1 transcripts. It promotes the formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues. Polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, bringing their disordered regions together, leading to phase separation. The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules, or neuronal RNA granules. YTHDF2 may also recognize and bind RNAs modified by C5-methylcytosine (m5C) and act as a regulator of rRNA processing. In the context of microbial infection, YTHDF2 promotes viral gene expression and replication of polyomavirus SV40 by binding to N6-methyladenosine (m6A)-containing viral RNAs. It also promotes viral gene expression and virion production of Kaposi's sarcoma-associated herpesvirus (KSHV) at some stage of the KSHV life cycle (in iSLK.219 and iSLK.BAC16 cells), again by binding to N6-methyladenosine (m6A)-containing viral RNAs. YTHDF2 interacts directly with CNOT1, promoting the recruitment of the CCR4-NOT complex. It also interacts with YTHDF3 and RIDA/HRSP12, leading to the recruitment of the ribonuclease P/MRP complex.

YTHDF2 is also known as CAHL, DF2, HGRG8, NY-REN-2.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing