YTHDF2, or YTH domain family member 2, is a protein with widespread influence on cellular processes. It impacts a substantial portion of genes, potentially affecting around 70% of them. Ongoing research continues to reveal its diverse functions and underlying mechanisms.
Understanding YTHDF2
YTHDF2 is an “m6A reader” protein that specifically identifies and attaches to N6-methyladenosine (m6A) modifications found on RNA molecules. The m6A modification involves adding a methyl group to an adenosine base within RNA, and this epigenetic mark is present in a significant portion of mammalian messenger RNAs, estimated to be between 20-50%. YTHDF2 is composed of approximately 570 amino acids, forming a structure with a unique m6A-binding pocket that facilitates its specific interaction with m6A-modified RNA.
YTHDF2 is found across various cell types, highlighting its widespread involvement in cellular operations. Its presence in diverse tissues, including the gonad, cerebellar vermis, and bone marrow cells, demonstrates its importance. By recognizing and binding modified RNA molecules, YTHDF2 regulates how genetic information is managed.
How YTHDF2 Regulates Gene Expression
Once YTHDF2 binds to an m6A-modified RNA molecule, its primary function is to promote RNA degradation. This process, known as mRNA decay, directly controls gene expression by removing specific RNA messages. By eliminating these RNA instructions, YTHDF2 influences which proteins are synthesized.
YTHDF2 facilitates this degradation through several mechanisms. One pathway involves recruiting the CCR4-NOT deadenylase complex to the m6A-containing RNA, which shortens the RNA’s poly(A) tail, initiating its decay. Another mechanism involves YTHDF2 cooperating with adaptor protein HRSP12 and the ribonuclease P/MRP complex to cleave target RNAs. This controlled RNA removal allows cells to adjust protein production in response to various signals.
YTHDF2’s Diverse Biological Functions
Beyond its molecular mechanism, YTHDF2 participates in diverse biological processes. It plays a role in cell differentiation, influencing how cells specialize, and is involved in embryonic development. For instance, YTHDF2 is necessary for proper oocyte maturation, impacting their ability to support early embryonic development.
The protein also contributes to immune responses, affecting the maturation, proliferation, and function of natural killer (NK) cells, which are part of the body’s defense system. YTHDF2 is implicated in cellular stress responses and regulates various aspects of RNA metabolism, including pre-ribosomal RNA processing. Its influence extends to processes like adipogenesis, where it can inhibit the differentiation of bone marrow stem cells into fat cells by degrading specific messenger RNAs.
YTHDF2’s Role in Human Diseases
Emerging research indicates that YTHDF2 dysregulation can contribute to various human diseases. In cancer, YTHDF2 has a complex role, acting as either a promoter or suppressor of tumor growth depending on the cancer type and cellular context. For example, it can inhibit cell proliferation and growth in hepatocellular carcinoma but promote proliferation and migration in prostate cancer.
YTHDF2 also influences viral infections, regulating viral replication. For instance, its binding to m6A sites on HIV-1 transcripts can enhance viral RNA stability, while its downregulation might augment antiviral responses. YTHDF2 is also investigated for its role in neurological disorders, affecting neural development and differentiation. Its impact on signaling pathways and gene expression makes it relevant for understanding disease pathogenesis and exploring therapeutic targets.