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MLL3/MLL4: Modifying Epigenetic Gene Regulators and Its
Role in Causing Cancer
By: Logan Icenhour
Epigenetic Overview
MLL/KMT2 Family of Histone Lysine Methyltransferases
So What’s The Big Deal?
MLL/KMT Identification of Structure and Domains
MLL3 = KMT2C
MLL4 = KMT2D
Discovery of COMPASS-like Function
• Evolutionarily conserved in Drosophila… of course!
TRR in Drosophila = Major H3K4
Monomethyltransferase
• H3K4me1 and H3K27ac enriched at actively transcribed genes
enhancer regions
• Global reduction of H3K4me1
Is TRR function homologous to MLL3/MLL4
function in humans and mice?
Altered
MLL3/MLL4
Function
Seen in a
Variety of
Cancer
Types
Transitional Cell Carcinoma (TCC) or Bladder Cancer
• Represents 90% of bladder cancers
• Non-muscle invasive and muscle invasive often harbor
Ras or TP53/RB gene mutations respectively but results
showed mutations in UTX to be just as likely in TCC
Implications of Mutant MLL3/MLL3 in Urothelial Cancer
Mechanism(s) by which MLL3/MLL4 mutations induce
cancer is not yet fully understood but work with mice
has provided some insight into this protein complexes
role as a coactivator of tumor suppressor p53
References
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Calo, Eliezer, and Joanna Wysocka. “Modification of Enhancer Chromatin: What, How and Why?”
Molecular cell 49.5 (2013): 10.1016/j.molcel.2013.01.038. PMC. Web. 15 Apr. 2015.
Ford, David, Adrew Dingwall. The cancer COMPASS: navigating the functions of MLL complexes in cancer.
Cancer Genetics.10.1016/j.cancergen.2015.01.00510.
GooYH,SohnYC,KimDH,etal.Activatingsignalcointegrator2 belongs to a novel steady-state complex that
contains a subset of Trithorax group proteins. Mol Cell Biol 2003;23:140e149.
Gui, Yaoting, Guangwu Guo, et al. "Frequent Mutations of Chromatin Remodeling Genes in Transitional
Cell Carcinoma of the Bladder." Nature Genetics 43.9 (2011): 875-78. Web. 10 Apr. 2015
Herz HM, Mohan M, Garruss AS, Liang K, Takahashi YH, Mickey K, Voets O, Verrijzer CP, Shilatifard A. 2012.
Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian
Mll3/Mll4. Genes Dev. 26:2604–2620
Lee J, Kim DH, Lee S, et al. A tumor suppressive coactivator complex of p53 containing ASC-2 and histone
H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4. Proc Natl Acad Sci U S A 2009;106:8513e8518.
Shen, Yongqing, Xiaoqiang Guo, Yuejia Wang, Wei Qiu, Yanzhong Chang, Aili Zhang, and Xianglin Duan.
"Expression and Significance of Histone H3K27 Demethylases in Renal Cell Carcinoma." BMC Cancer 12.1
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