KMT2A
Description
The KMT2A (lysine methyltransferase 2A) is a protein-coding gene located on chromosome 11.
Histone-lysine N-methyltransferase 2A, also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia 1 (MLL1), or zinc finger protein HRX (HRX), is an enzyme that in humans is encoded by the KMT2A gene. MLL1 is a histone methyltransferase deemed a positive global regulator of gene transcription. This protein belongs to the group of histone-modifying enzymes comprising transactivation domain 9aaTAD and is involved in the epigenetic maintenance of transcriptional memory. Its role as an epigenetic regulator of neuronal function is an ongoing area of research.
== Function ==
=== Transcriptional regulation === KMT2A gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. Enriched in the nucleus, the MLL1 enzyme trimethylates H3K4 (H3K4me3). It also upregulates mono- and dimethylation of H3K4. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C (~180 kDa) and MLL-N (~320 kDa).
KMT2A is a histone methyltransferase that plays a crucial role in early development and hematopoiesis. It is the catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates methylation of lysine 4 of histone H3 (H3K4me) and acetylation of lysine 16 of histone H4 (H4K16ac). KMT2A catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the epsilon-amino group of lysine 4 of histone H3 (H3K4) via a non-processive mechanism. It primarily forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair occur. KMT2A has weak methyltransferase activity alone and requires other components of the MLL1/MLL complex for full activity. It has no activity towards histone H3 phosphorylated on threonine 3, less activity towards H3 dimethylated on arginine 8 or lysine 9, but higher activity towards H3 acetylated on lysine 9. KMT2A binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state. It is required for the transcriptional activation of HOXA9. KMT2A promotes PPP1R15A-induced apoptosis. It plays a critical role in controlling circadian gene expression and is essential for the transcriptional activation mediated by the CLOCK-BMAL1 heterodimer. It establishes a permissive chromatin state for circadian transcription by mediating a rhythmic methylation of lysine 4 of histone H3 (H3K4me). This histone modification directs the circadian acetylation at H3K9 and H3K14, allowing the recruitment of CLOCK-BMAL1 to chromatin. KMT2A also exhibits auto-methylation activity on cysteine 3882 in the absence of a histone H3 substrate.
KMT2A is also known as ALL-1, ALL1, CXXC7, GAS7, HRX, HTRX, HTRX1, MLL, MLL1, MLL1A, TRX1, WDSTS.
