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Normal gene expression is controlled, in part, through multiple regulatory systems which coordinate transcription. This includes transcription factors that recruit enzymes to express genes as well as an evolving understanding of the 3-dimensional chromatin architecture which brings together either DNA enhancer regions to activate genes or DNA insulation regions to silence genes. Structural scaffold proteins such at CTCF and the cohesin complex are essential in maintaining the integrity of local DNA structural interactions within defined neighborhoods known as topologically associating domains (TADs). These proteins provide dynamic structure within the TAD which is essential in influencing dynamic cell-type specific transcriptional programs. Genes which contribute to transcriptional regulation, including members of the cohesin complex, are frequently mutated in human cancers, including acute myeloid leukemia (12-20%), glioblastoma multiforme (5%), bladder cancer (20-35%) and Ewing sarcoma (40-50%).
The functional consequences of chromatin structure in regulating lineage-specification, signal-dependent responses, and local/distant DNA structure has not been fully elucidated, however, our recent work has established the requirement of suitable chromatin architecture for the function of cell-type specific transcription factors to activate gene responsible for blood formation bone marrow stem cell differentiation. Our laboratory uses genetic mouse models and primary patient samples to understand the role of altered chromatin architecture as a regulator of gene expression/gene silencing that maintain the balance of hematopoietic stem cell self-renewal with differentiation and blood formation.
Viny AD, Levine RL. Drug Modulation by Nuclear Condensates. Science. 2020 Jun 19; 6497(368): 1314-1315.
Kishtagari A, Levine RL, Viny AD.Driver Mutations in Acute Myeloid Leukemia. Curr Opin Hematol. 2020 March;27(2): 49-57. PMID: 31972687
Viny AD, Bowman RL, Liu Y, Lavallée VP, Eisman S, Xiao W, Durham B, Navitski A, Park J, Braunstein S, Alija B, Karzai A, Csete IS, Witkin M, Azizi E, Baslan T, Ott CJ, Pe’er D, Dekker J, Koche R, Levine RL. Cohesin members Stag1 and Stag2 display distinct roles in chromatin accessibility and topological control of HSC self-renewal and differentiation. Cell Stem Cell November 7, 25(5): 682-696 e688. PMID: 31495782
Viny AD, Levine RL. Cohesin mutations in myeloid malignancies made simple. Curr Opin Hematol. 2017 Dec 22. PubMed PMID: 29278534
Viny AD, Levine RL. Roads Diverge--A Robert Frost View of Leukemia Development. N Engl J Med. 2016 Jun 9;374(23):2282-4. PubMed PMID: 27276567.
van Galen P, Viny AD, Ram O, Ryan RJH, Cotton MJ, Donohue L, Sievers C, Drier Y, Liau BB, Gillespie SM, Carroll KM, Cross MB, Levine RL, Bernstein BE. A Multiplexed System for Quantitative Comparisons of Chromatin Landscapes. Molecular Cell. 2016 Jan 7 PMID:26687680
Viny AD*, Ott CJ*, Spitzer B, Rivas M, Meydan C, Papalexi E, Yelin D, Shank K, Reyes J, Chiu A, Romin Y, Boyko V, Thota S, Maciejewski JP, Melnick A, Bradner JE, Levine RL. Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis. Journal of Experimental Medicine, 2015 Oct 5 PMID: 2648361.
Thota S*, Viny AD*, Makishima H, Spitzer B, Radivoyevitch T, Przychodzen B, Sekeres MA, Levine RL, Maciejewski JP. Genetic alterations of the cohesin complex genes in myeloid malignancies, Blood, 2014 Sept 11;124(11): 1790-8. PMID: 25006131