Ali Shilatifard

Ali Shilatifard
Institutions	Northwestern University Feinberg School of Medicine Stowers Institute for Medical Research, St. Louis University School of Medicine
Alma mater	University of Georgia, Athens University of Oklahoma School of Medicine Kennesaw State University
Notable awards	Elected Fellow of the American Association for the Advancement of Science (AAAS) ASBMB-AMGEN Award
Spouse	Laura Shilatifard
Children	4

Ali Shilatifard is an American biochemist/molecular biologist. He is considered a leader in the field of transcription and chromatin biology and leukemia research; and a pioneer in the field of epigenetics. Shilatifard is the Robert Francis Furchgott Professor and Chairman of the Department of Biochemistry and Molecular Genetics at the Northwestern University Feinberg School of Medicine. He serves as a Senior Editor for the journal Science, Deputy Editor for Science Advances, and as an Editor for the journal Molecular and Cellular Biology and serves on the Board of Reviewing Editors for eLife. Shilatifard’s laboratory has contributed significantly to the molecular understanding of the cause of childhood leukemia through chromosomal translocations, the role of ELL in this process, and the discovery of the Super Elongation Complex as being a central complex linking MLL translocations into a diverse number of genes to leukemic pathogenesis. Shilatifard’s studies and contributions are highly cited across many scientific fields.^[1] Shilatifard was recognized as a Jane Coffin Childs Fellow; recipient of the ASBMB-AMGEN Young Investigator Award; as a Scholar of the Leukemia and Lymphoma Society; and by the American Cancer Society. Shilatifard serves on the Scientific Advisory Boards of the Max Planck Society; Genentech; and Keystone Symposia.

Ali Shilatifard, Ph.D. Institute: Northwestern University Feinberg School of Medicine

Fields: Cancer Biology, Epigenetics, Transcription, Chromatin

Residence: United States of America

Alma Mater: University of Georgia; University of Oklahoma

Biography

Shilatifard developed his lifelong love of science as a young boy working with and observing his grandfather,^[2] a physician/scientist and Professor of Medicine of the University of Tehran. Shilatifard moved to the United States in 1984 where he began his study of organic chemistry at Kennesaw State University in Georgia. He began to work on his doctoral degree in biochemistry at the University of Georgia, Athens. Shilatifard completed and received his Ph.D. from the University of Oklahoma where his then mentor, Dr. Richard Cummings, had moved his program. As a Jane Coffin Childs Postdoctoral Fellow at the Oklahoma Medical Research Foundation, Shilatifard made a seminal contribution to the field of leukemia biology by identifying the first function of any of the MLL translocation partners found in leukemia ^[3] and proposed that transcriptional elongation control is central to leukemia pathogenesis. Shilatifard began his independent lab in the Edward A. Doisy Department of Biochemistry and Molecular Biology at the St. Louis University School of Medicine, where he identified the first histone H3 lysine 4 (H3K4) methylase in Saccharomyces cerevisiae: which he named Set1/COMPASS;^[4][5] and defined the pathway of histone H3K4 methylation which is highly conserved from yeast to human.^[6][7] Shilatifard has presented over 400 invited lectures at scientific meetings and universities in the U.S. and at international institutes and universities. Shilatifard moved his program to the Stowers Institute for Medical Research where he was an Investigator from 2007-2014. Shilatifard left the Stowers Institute in 2014 to become the Robert Francis Furchgott Professor and Chairman of the Department of Biochemistry and Molecular Genetics of the Northwestern University Feinberg School of Medicine. Ali Shilatifard is married to Laura Shilatifard with four children.

Major discoveries

• 1996: Shilatifard and colleagues identified the in vitro biochemical function for the first MLL-translocation partner as a RNA polymerase II elongation factor linking transcriptional elongation control to leukemic pathogenesis through MLL translocations.^[3]
• 2001: Shilatifard and colleagues provided the first in vivo properties of ELL as an RNA polymerase II elongation factor.^[8]
• 2001-2002: Report of the first purification of the Set1/COMPASS, the yeast homologue of the MLL complex in human cells and identification of the histone H3K4 methylase activity of the complex.^[4][5]
• 2002: Development of a biochemical screen in yeast identifying a role for Rad6 and H2B monoubiquitination in the regulation of Set1/COMPASS H3K4 methylase function.^[9]
• 2003: Shilatifard’s laboratory reported the first identification of Bre1 as the E3 ligase functioning in the regulation of histone H2B monoubiquitination and H3K4 methylation by COMPASS.^[10]
• 2003: Shilatifard’s laboratory reported the first identification of a role for the components of the elongation complex, the Paf1 complex, in regulation of histone H2B monoubiquitination and histone H3K4 methylation, linking transcriptional elongation control to the regulation of histone modifications.^[11][12]
• 2005: Defining the molecular role of factors involved in H3K4 methylation by Set1/COMPASS through biochemical screens.^[13][14]
• 2007: Shilatifard and colleagues reported the identification of the role of the yeast Cps35, the homologue of the human Wdr82 protein, in the regulation of COMPASS function.^[7]
• 2008: Shilatifard’s laboratory reported the development of a comprehensive library of alanine scanning mutations for the entire yeast histone H3, H4, H2A and H2B.^[15]
• 2010: First biochemical purification of the Dot1 complex (DotCom) and demonstration of the function of the complex in the Wnt signaling pathway.^[16]
• 2010: Shilatifard’s laboratory reported the first biochemical purification of the MLL-chimeras and identification and molecular characterization of the Super Elongation Complex (SEC) and demonstration that many of the MLL partners are found within SEC, regulating the elongation stage of transcription This study demonstrated that the misregulation of the elongation step of transcription could be the cause of childhood leukemia through MLL translocations.^[17][18]
• 2011: Shilatifard and colleagues demonstrated that SEC contains the most active version of P-TEFb and is required for rapid transcriptional induction in the presence or absence of paused RNA Polymerase II.^[19]
• 2012: Shilatifard’s laboratory reported for the first time a role for Drosophila Trr and its mammalian homologues MLL3/MLL4 in enhancer monomethylation and the regulation of enhancer promoter communications.^[20]
• 2013: Shilatifard’s laboratory reported the identification of the role for ELL3 in enhancer marking in embryonic stem cells and in priming future gene expression. This report raised the possibility that transcription factors could prime gene expression by marking enhancers in ES cells or even as early as in the germ cell state.^[21]
• 2014: Shilatifard's laboratory took advantage of Drosophila genetics to define the roles of histone H3-lysine-to-methionine mutations, specifically for H3K27M in the pathogenesis of pediatric diffuse intrinsic pontine glioma (DIPG), and demonstrated that hyperacetylation of H3K27M bearing nucleosomes and the subsequent recruitment of BRD1 and BRD4 are the major causes of DIPG. In this study, Shilatifard and colleagues proposed the use of BET-domain inhibitors for targeted therapeutics of DIPG. ^[22]
• 2015: Shilatifard and colleagues identified a central role for the Paf1 complex and the Super Elongation Complex in the maintenance of the paused state of RNA Polyemerase II during development. ^[23]

Honors and Awards

• 2016: Elected Fellow of the American Association for the Advancement of Science (AAAS)
• 2016: Martin E. and Gertrude G. Walder Award for Research Excellence Recipient
• 2015: Inaugural Recipient of the National Cancer Institute Outstanding Investigator Award (R35)
• 2007: Innovation Award, Academy of Science, St. Louis
• 2006: American Society for Biochemistry and Molecular Biology ASBMB-AMGEN Award
• 2006: American Cancer Society Award of Excellence
• 2006: Selected as Leukemia & Lymphoma Society Stohlman Scholar (not present at meeting, unable to accept)
• 2002: Recipient of the Sword of the American Cancer Society
• 2001-2006: Scholar of the Leukemia and the Lymphoma Society
• 1999-2002: Edward Mallinckrodt, Jr. Young Investigator
• 1995-1997: Jane Coffin Childs Postdoctoral Fellow

References

1. Ali Shilatifard's publications indexed by Google Scholar
2. Ali Shilatifard: Discovering the roots of cancer, St. Louis Business Journal, Jul 23, 2006
3. Shilatifard et al, An RNA polymerase II elongation factor encoded by the human ELL gene, Science, Mar 29;271(5257):1873-6. (1996)
4. Miller, T. et al. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc Natl Acad Sci U S A 98, 12902-12907 (2001)
5. Krogan, N. J. et al. COMPASS, a histone H3 (Lysine 4) methyltransferase required for telomeric silencing of gene expression. J Biol Chem 277, 10753-10755, doi:10.1074/jbc.C200023200[pii] (2002)
6. Smith, E. & Shilatifard, A. The chromatin signaling pathway: diverse mechanisms of recruitment of histone-modifying enzymes and varied biological outcomes. Mol Cell 40, 689-701, doi:S1097-2765(10)00917-2 [pii]10.1016/j.molcel.2010.11.031 (2010)
7. Lee, J. S. et al. Histone crosstalk between H2B monoubiquitination and H3 methylation mediated by COMPASS. Cell 131, 1084-1096, doi:S0092-8674(07)01350-5 [pii]10.1016/j.cell.2007.09.046 (2007)
8. Gerber et al Drosophila ELL is associated with actively elongating RNA polymerase II on transcriptionally active sites in vivo.EMBO J. 2001 Nov 1;20(21):6104-14.
9. Dover, J. et al. Methylation of histone H3 by COMPASS requires ubiquitination of histone H2B by Rad6. J Biol Chem 277, 28368-28371 (2002)
10. Wood, A. et al. Bre1, an E3 ubiquitin ligase required for recruitment and substrate selection of Rad6 at a promoter. Mol Cell 11, 267-274 (2003)
11. Krogan, N. J. et al. The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation. Mol Cell 11, 721-729 (2003)
12. Wood, A., Schneider, J., Dover, J., Johnston, M. & Shilatifard, A. The Paf1 complex is essential for histone monoubiquitination by the Rad6-Bre1 complex, which signals for histone methylation by COMPASS and Dot1p. J Biol Chem 278, 34739-34742 (2003)
13. Wood, A., Schneider, J., Dover, J., Johnston, M. & Shilatifard, A. The Bur1/Bur2 complex is required for histone H2B monoubiquitination by Rad6/Bre1 and histone methylation by COMPASS. Mol Cell 20, 589-599 (2005)
14. Schneider, J. et al. Molecular regulation of histone H3 trimethylation by COMPASS and the regulation of gene expression. Mol Cell 19, 849-856 (2005)
15. Nakanishi, S. et al. A comprehensive library of histone mutants identifies nucleosomal residues required for H3K4 methylation. Nat Struct Mol Biol 15, 881-888 (2008)
16. Mohan, M. et al. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes & development 24, 574-589, doi:10.1101/gad.1898410 (2010)
17. Lin et al, AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras can link transcription elongation to leukemia. Mol Cell 37, 429-437 (2010)
18. Smith et al, The Super Elongation Complex (SEC) in development and disease. Gen Dev 25, 661-672 (2011)
19. Lin, C. et al. Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC). Genes & development 25, 1486-1498, doi:10.1101/gad.2059211 (2011)
20. Herz, H. M. et al. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes & development 26, 2604-2620, doi:10.1101/gad.201327.112 (2012)
21. Lin, C., Garruss, A. S., Luo, Z., Guo, F. & Shilatifard, A. The RNA Pol II Elongation Factor Ell3 Marks Enhancers in ES Cells and Primes Future Gene Activation. Cell, doi:10.1016/j.cell.2012.12.015 (2013)
22. Herz, H-M., Morgan, M.A., Gao, X., Jackson, J., Rickels, R., Swanson, S. K., Florens, L., Washburn, M. P., Eissenberg, J. C., and Shilatifard, A. (2014) Histone H3 Lysine-to-methionine mutants aas a paradigm to study chromatin signaling 2014 Aug 29;345(6200):1065-70. doi: 10.1126/science.1255104.
23. Chen, F., Woodfin, A. R., Gardini, A., Rickels, R., Marshall, S. A., Smith, E. R., Shiekhattar, R., and Shilatifard, A. (2015). PAF1, a molecular regulator of promoter-proximal pausing by RNA polymerase II. Cell, 62,1003-1015.

External links

• Northwestern University Feinberg School of Medicine
• Shilatifard Publications
• Stowers Institute for Medical Research - PBS Local on YouTube
• Ali Shilatifard on Epigenetic Marks and Cancer Drugs on YouTube
• Molecular and Cellular Biology