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

• 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 (2012): 470. Web. 10 Apr. 2015