METTL3

Official Full Name

methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit

Organism

Homo sapiens

Gene ID

56339

Background

This gene encodes the 70 kDa subunit of MT-A which is part of N6-adenosine-methyltransferase. This enzyme is involved in the posttranscriptional methylation of internal adenosine residues in eukaryotic mRNAs, forming N6-methyladenosine. [provided by RefSeq, Jul 2008]

Synonyms

M6A; IME4; Spo8; MT-A70; hMETTL3

Cat.No.	Product Name	Price
CSC-DC009440	Panoply™ Human METTL3 Knockdown Stable Cell Line	Inquiry
CSC-SC009440	Panoply™ Human METTL3 Over-expressing Stable Cell Line	Inquiry
CSC-RO01315	Mouse Mettl3 Stable Cell Line - NIT-1	Inquiry

Cat.No.	Product Name	Price
AD09881Z	Human METTL3 adenoviral particles	Inquiry
LV18138L	human METTL3 (NM_019852) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH185753	shRNA set against Rat Mettl3(NM_001024794.1)	Inquiry
SHH185717	shRNA set against Mouse Mettl3(NM_019721.2)	Inquiry
SHH185735	shRNA set against Human METTL3(NM_019852.3)	Inquiry
SHH340823	shRNA set against Mouse METTL3 (NM_019721.2)	Inquiry
SHH340827	shRNA set against Rat METTL3 (NM_001024794.1)	Inquiry
SHW017934	shRNA set against Danio rerio METTL3 (NM_212780)	Inquiry

Cat.No.	Product Name	Price
CDCL132153	Mouse Mettl3 ORF clone (NM_019721.2)	Inquiry
CDCR370739	Rat Mettl3 ORF Clone(NM_001024794.1)	Inquiry
CDFR003685	Rat Mettl3 cDNA Clone(NM_001024794.1)	Inquiry
MiUTR1H-06224	METTL3 miRNA 3'UTR clone	Inquiry
MiUTR1M-07065	METTL3 miRNA 3'UTR clone	Inquiry
MiUTR1R-03767	METTL3 miRNA 3'UTR clone	Inquiry
CDCB179409	Danio rerio METTL3 ORF Clone (NM_212780)	Inquiry
CDCB185644	Rabbit METTL3 ORF clone (XM_002718051.2)	Inquiry
CDCR304791	Human METTL3 ORF Clone(NM_019852.3)	Inquiry
CDCS419008	Human METTL3 ORF Clone (BC052244)	Inquiry

Detailed Information

Detailed Information

The METTL3 gene encodes the catalytic core subunit of the N6-methyladenosine (m6A) methyltransferase complex. This complex primarily catalyzes the deposition of m6A modifications on internal adenosine residues of eukaryotic messenger RNAs (mRNAs), the most abundant and widespread internal chemical modification in eukaryotic mRNA to date. METTL3 forms a stable heterodimer with METTL14, in which METTL3 provides the primary catalytic activity, while METTL14, although catalytically inactive, serves as a structural scaffold, recognizing RNA substrates and maintaining complex stability. Additional accessory proteins, such as WTAP, participate in the complex to ensure precise m6A deposition at specific genomic loci. METTL3 is tightly regulated and distributed in both the nucleus and cytoplasm, indicating its involvement in multiple gene expression processes ranging from nuclear post-transcriptional processing to cytoplasmic translation regulation.

Figure 1. METTL3-dependent biological functions in cells. (Hu C, et al., 2022)

Biological Significance

METTL3-mediated m6A modification represents a novel layer of gene expression regulation, often referred to as "RNA epigenetics" or "epitranscriptomics." m6A modifications are not randomly distributed but enriched near stop codons, 3' untranslated regions (UTRs), and long internal exons, suggesting diverse functional outcomes. These marks do not dictate mRNA fate directly but serve as molecular tags recognized by specific "reader" proteins, which mediate downstream effects. For example, YTHDF proteins primarily promote the degradation of m6A-modified mRNAs, YTHDC1 participates in selective splicing and nuclear export, while YTHDF1 and YTHDF3 may enhance translation efficiency of specific mRNAs.

As the core "writer" of m6A, METTL3 profoundly influences cellular physiology by marking a broad spectrum of mRNAs. It is essential for maintaining pluripotency and differentiation in embryonic stem cells by methylating key pluripotency factor transcripts and promoting their degradation, thereby facilitating exit from the naïve state and initiation of differentiation programs. In hematopoiesis, METTL3 is critical for stem cell self-renewal and lineage differentiation. During neurodevelopment, m6A regulates neural stem cell proliferation and differentiation, controlling cortical neurogenesis precisely. METTL3 is also involved in circadian rhythm regulation, DNA damage response, T cell homeostasis and differentiation, and primary microRNA processing. Notably, METTL3 exhibits m6A-independent functions, directly interacting with translation initiation machinery to enhance the translation of specific mRNAs, which may contribute to its oncogenic activity. Overall, METTL3 dynamically and reversibly modifies the transcriptome, acting as a central regulator of cell identity, fate decisions, and stress responses.

Clinical Relevance

METTL3's clinical significance stems from its frequent dysregulation in human cancers, making it a promising therapeutic target and biomarker. Its expression is often elevated in various leukemias, such as acute myeloid leukemia (AML), and in solid tumors, including lung, liver, and colorectal cancers. Its oncogenic mechanisms include m6A-dependent stabilization or enhanced translation of oncogenic mRNAs, as well as m6A-independent promotion of oncogene translation. Additionally, METTL3 modifies transcripts involved in tumor metabolism and immune evasion, shaping a microenvironment conducive to tumor growth. Consequently, the development of small-molecule inhibitors targeting METTL3's methyltransferase activity has become an active area in cancer therapy.

Researchers and pharmaceutical companies are actively screening and optimizing compounds that specifically inhibit METTL3, aiming to globally reduce m6A levels in tumor cells, disrupt aberrant gene expression networks, suppress proliferation, and induce apoptosis. Preclinical studies demonstrate that these inhibitors effectively inhibit AML growth in vitro and in animal models. Challenges remain in defining a therapeutic window, as METTL3 is also critical for normal physiological processes, and systemic inhibition may cause significant toxicity. Strategies may include cancer-type-specific targeted delivery or identifying synthetic lethality partners. Beyond oncology, METTL3 shows potential relevance in metabolic disorders, cardiovascular disease, and neurodegenerative diseases, where m6A dysregulation contributes to pathology. As a biomarker, measuring global or gene-specific m6A levels in tumors or biofluids may provide valuable insights for diagnosis, stratification, and prognosis. In summary, METTL3, as a central epitranscriptomic regulator, represents a promising, albeit early-stage, therapeutic target for difficult-to-treat cancers and other diseases.

References

Liu J, Yue Y, Han D, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10(2):93–95.
Barbieri I, Tzelepis K, Pandolfini L, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature. 2017;552(7683):126–131.
Deng X, Su R, Weng H, Huang H, et al. RNA N6-methyladenosine modification in cancers: current status and perspectives. Cell Res. 2018;28(5):507–517.
Hu C, Liu J, Li Y, et al. Multifaceted Roles of the N⁶-Methyladenosine RNA Methyltransferase METTL3 in Cancer and Immune Microenvironment. Biomolecules. 2022 Jul 28;12(8):1042.

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