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Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
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Visitor (IP on July 06, 2011 wrote:
 Typo on figure 1: transcativation 

The mixed lineage leukemia (MLL) gene encodes a complex DNA-binding protein with histone H3 lysine 4 (H3K4) methylation activity (Fig. 1).[1] H3K4 methylation is associated with transcriptionally active chromatin, and MLL is therefore thought to epigenetically control gene expression through modification of chromatin structure rather than classical sequence-specific DNA-binding transcription factor function. In addition to its H3K4 methyltransferase activity, MLL has also been shown to bind to specific CpG clusters within gene loci protecting them from methylation ultimately resulting in maintenance of transcript expression.[2] MLL is a structural and functional homolog of Drosophila trithorax, a homeotic regulator, and has been implicated in epigenetic regulation of transcription that is critical for normal embryonic development and hematopoiesis as well as the pathogenesis of leukemia. [3] [4] The MLL protein is post-translationally cleaved by the protease taspase I into two subunits that directly interact and form the core structure of the MLL multi-protein transcriptional complex (Fig. 2). The complex contains additional proteins that mediate DNA-binding, histone modification, transcription factor and co-regulator function and RNA-processing. [5] Among the most widely studied targets of MLL transcriptional regulation are Hox genes. However, MLL associates with thousands of promotors, typically of genes occupied by RNA polymerase II which is required for normal transcriptional initiation and elongation, providing further evidence for MLL's global role as a transcriptional regulator.

The MLL gene is a frequent target for chromosomal rearrangements found in clinically aggressive human acute leukemias of myeloid, lymphoid or mixed lineage in children and adults. Reciprocal chromosomal translocations fuse the N-terminal ~1400 amino acids of MLL in frame to one of over 50 partner proteins of various function including nuclear transcription factors and cytoplasmic proteins. All MLL fusion proteins retain the amino-terminal AT-hooks and the CxxC domain of MLL, thus preserving DNA binding activity. In contrast, the plant homeodomain fingers, a region with transactivating potential, and the H3K4 methyltransferase domain are lost. [6] Although deletion of the carboxy-terminal region of MLL would be predicted to result in abrogation of transactivation and histone methyltransferase functions, transforming MLL fusion proteins act as transcriptional regulators that can bind DNA and induce aberrant expression of downstream MLL targets such as Hox genes. This points to a disturbance in the epigenetic regulation of gene expression as the main mechanism for leukemogenesis induced by MLL rearrangements. The precise mechanism for this aberrant transcriptional activity is not known, but involves formation of a transcriptional core complex by the chimeric MLL oncoprotein and recruitment of other chromatin modifiers including the H3K79 methyltransferase hDOT1L and the H4R3 methyltransferase PRMT1.[7][8]

  1. Tkachuk DC et al. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell, 71(4):691-700. (PMID 1423624)
  2. Erfurth FE et al. MLL protects CpG clusters from methylation within the Hoxa9 gene, maintaining transcript expression. Proc. Natl. Acad. Sci. U.S.A., 105(21):7517-22. (PMID 18483194)
  3. Yu BD et al. Altered Hox expression and segmental identity in Mll-mutant mice. Nature, 378(6556):505-8. (PMID 7477409)
  4. Hess JL et al. Defects in yolk sac hematopoiesis in Mll-null embryos. Blood, 90(5):1799-806. (PMID 9292512)
  1. Daser A and Rabbitts TH. The versatile mixed lineage leukaemia gene MLL and its many associations in leukaemogenesis. Semin. Cancer Biol., 15(3):175-88. (PMID 15826832)
  2. Krivtsov AV and Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat. Rev. Cancer, 7(11):823-33. (PMID 17957188)
  3. Okada Y et al. hDOT1L links histone methylation to leukemogenesis. Cell, 121(2):167-78. (PMID 15851025)
  4. Cheung N et al. Protein arginine-methyltransferase-dependent oncogenesis. Nat. Cell Biol., 9(10):1208-15. (PMID 17891136)
FIGURE 1 Schematic representation of the MLL gene
The 37 exons of the MLL gene encode a nuclear protein of 3,969 amino acids with a molecular weight of 421 kDa. At the N-terminus, there are three AT-hooks, two speckled nuclear localization signals (SNL), and a transcriptional repression domain (TRD) consisting of RD1 (containing a CXXC domain) and RD2, followed by four plant homeodomain (PHD) finger motifs separated by an atypical bromodomain. Further C-terminal follows a transcriptional transcativation domain (TAD), and the SET (Su(var)3-9, enhancer-of-zeste, trithorax) domain with H3K4 methyltransferase activity. Post-translationally, taspase I cleaves MLL after amino acid 2,666 (cleavage site 1 (CS1)) and 2,718 (CS2) generating two subunits (MLLN p300 and MLLC p180) that form a complex by direct interaction of the FYRN and FYRC domains.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.