- Erica Ballabio
- Jon Kerry
- Phil North
- Marta Tapia
- Ross Thorne
- Kowalczyk M S, Hughes J R, Garrick D, Lynch M D, Sharpe J A, Sloane-Stanley J A, McGowan S J, De G o, Hosseini M, Vernimmen D, Brown J M, Gray N E, Collavin L, Gibbons R J, Flint J, Taylor S, Buckle V J, Milne T A, Wood W G, and Higgs D R (2012) Intragenic Enhancers Act as Alternative Promoters. Mol Cell.
- Ruthenburg Alexander J, Li Haitao, Milne Thomas A, Dewell Scott, McGinty Robert K, Yuen Melanie, Ueberheide Beatrix, Dou Yali, Muir Tom W, Patel Dinshaw J, and Allis C D (2011) Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell, 145(5):692-706.
- Biswas Debabrata, Milne Thomas A, Basrur Venkatesha, Kim Jaehoon, Elenitoba-Johnson Kojo SJ, Allis C D, and Roeder Robert G (2011) Function of leukemogenic mixed lineage leukemia 1 (MLL) fusion proteins through distinct partner protein complexes. Proc Natl Acad Sci U S A, 108(38):15751-6.
- Wang Zhanxin, Song Jikui, Milne Thomas A, Wang Gang G, Li Haitao, Allis C D, and Patel Dinshaw J (2010) Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression. Cell, 141(7):1183-94.
- Milne Thomas A, Kim Jaehoon, Wang Gang G, Stadler Sonja C, Basrur Venkatesha, Whitcomb Sarah J, Wang Zhanxin, Ruthenburg Alexander J, Elenitoba-Johnson Kojo SJ, Roeder Robert G, and Allis C D (2010) Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol Cell, 38(6):853-63.
|Department||Weatherall Institute of Molecular Medicine|
The most common leukaemic disruptions of the MLL1 gene are chromosome translocations that fuse the N terminus of MLL1 in frame with over 40 different partner genes. The majority of all MLL1 gene fusions are accounted for by fusions with the AF4, AF9, ENL, ELL, AF10 or AF6 genes, making this the most important group of MLL1 fusion partners. Recent work has suggested that wild type MLL1 and MLL1 fusion proteins cooperate in leukaemogenesis by together causing aberrant epigenetic profiles at target genes in vivo. MLL1 controls gene activation in part by methylating histone 3 (H3) at lysine 4 while MLL1 fusion proteins add to this epigenetic profile by recruiting the Dot1 protein and methylating the H3 lysine 79 (H3K79) residue, as well as recruiting components of a transcription elongation complex. Despite the conservation of biochemical interactions for these proteins, different MLL1 fusion proteins cause different leukaemias in humans. Thus it a combination of the specific fusion partner and the cell type where the fusion is expressed that determines the resulting leukaemia.
A major question in the field is how MLL1 and MLL1 fusion proteins are recruited to in vivo target genes such as HOXA9 in normal and leukaemic cells. Instead of a single interaction being responsible for gene specific targeting, we have found that chromatin proteins are recruited to gene targets through multiple interdependent weak or transient interactions that together produce stable binding as well as specificity. Such a "multivalency code", where no single interaction is sufficient for gene specific targeting and stable binding, could also potentially allow for dynamic regulation of binding during haematopoietic differentiation. Recently, we have identified some multivalent interactions that control the recruitment of both wild type MLL1 and MLL1 fusion proteins to the HOXA9 locus.
To further analyze this important problem, we are attempting to answer three interrelated questions: 1) Do different MLL1 fusion proteins regulate unique gene targets in haematopoietic stem cells and in leukaemogenesis? 2) How does wild type MLL1 contribute to leukaemogenesis on a molecular level? and 3) how does gene activation and the binding of transcription factors control the specific recruitment of MLL1 and MLL1 fusion proteins to target genes in haematopoietic stem cells and in leukaemogenesis?