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Start Over Author "Smil D" Topic histones
3 results on '"Smil D"'

1. A chemical biology toolbox to study protein methyltransferases and epigenetic signaling.

Author

Scheer S, Ackloo S, Medina TS, Schapira M, Li F, Ward JA, Lewis AM, Northrop JP, Richardson PL, Kaniskan HÜ, Shen Y, Liu J, Smil D, McLeod D, Zepeda-Velazquez CA, Luo M, Jin J, Barsyte-Lovejoy D, Huber KVM, De Carvalho DD, Vedadi M, Zaph C, Brown PJ, and Arrowsmith CH

Subjects
Animals, Cell Differentiation drug effects, Cell Differentiation genetics, Enzyme Assays methods, Epigenomics methods, HEK293 Cells, Histone-Lysine N-Methyltransferase, Humans, Jurkat Cells, Methylation drug effects, Methyltransferases antagonists & inhibitors, Methyltransferases metabolism, Mice, Inbred C57BL, Protein Methyltransferases metabolism, Protein Processing, Post-Translational genetics, Th1 Cells drug effects, Th1 Cells physiology, Enzyme Inhibitors pharmacology, Epigenesis, Genetic drug effects, Histones metabolism, Protein Methyltransferases antagonists & inhibitors, Protein Processing, Post-Translational drug effects
Abstract

Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4 + T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond.

Published
2019
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2. Functional interdependence of BRD4 and DOT1L in MLL leukemia.

Author

Gilan O, Lam EY, Becher I, Lugo D, Cannizzaro E, Joberty G, Ward A, Wiese M, Fong CY, Ftouni S, Tyler D, Stanley K, MacPherson L, Weng CF, Chan YC, Ghisi M, Smil D, Carpenter C, Brown P, Garton N, Blewitt ME, Bannister AJ, Kouzarides T, Huntly BJ, Johnstone RW, Drewes G, Dawson SJ, Arrowsmith CH, Grandi P, Prinjha RK, and Dawson MA

Subjects
Acetylation, Animals, B-Lymphocytes metabolism, B-Lymphocytes pathology, Cell Cycle Proteins, Cell Proliferation, Chromatin chemistry, Chromatin metabolism, Clinical Trials as Topic, Disease Models, Animal, Female, Histone-Lysine N-Methyltransferase, Histones metabolism, Humans, Leukemia, Biphenotypic, Acute metabolism, Leukemia, Biphenotypic, Acute pathology, Male, Methyltransferases antagonists & inhibitors, Methyltransferases metabolism, Mice, Mice, Inbred C57BL, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins metabolism, Primary Cell Culture, Protein Binding, Proteomics methods, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, T-Lymphocytes metabolism, T-Lymphocytes pathology, Transcription Factors antagonists & inhibitors, Transcription Factors metabolism, Transcription, Genetic, Gene Expression Regulation, Leukemic, Histones genetics, Leukemia, Biphenotypic, Acute genetics, Methyltransferases genetics, Nuclear Proteins genetics, Transcription Factors genetics
Abstract

Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.

Published
2016
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3. MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.

Author

Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, Remke M, Li R, Takayama N, Desai K, Lee L, Lan X, Park NI, Barsyte-Lovejoy D, Smil D, Sturm D, Kushida MM, Head R, Cusimano MD, Bernstein M, Clarke ID, Dick JE, Pfister SM, Rich JN, Arrowsmith CH, Taylor MD, Jabado N, Bazett-Jones DP, Lupien M, and Dirks PB

Subjects
Adolescent, Adult, Animals, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms mortality, Brain Neoplasms pathology, Cell Differentiation, Cell Proliferation, Child, Child, Preschool, DNA Methylation, DNA-Binding Proteins genetics, Drug Design, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma mortality, Glioblastoma pathology, Histones genetics, Humans, Kaplan-Meier Estimate, Mice, Inbred NOD, Mice, SCID, Molecular Targeted Therapy, Mutation, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Prognosis, RNA Interference, Signal Transduction, Time Factors, Transfection, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Young Adult, Brain Neoplasms metabolism, Cell Self Renewal drug effects, Chromatin Assembly and Disassembly drug effects, DNA-Binding Proteins metabolism, Glioblastoma metabolism, Histones metabolism, Neoplastic Stem Cells metabolism
Abstract

Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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