Nicholas J Dyson

Harvard University, Cambridge, Massachusetts, United States

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Publications (131)1388.75 Total impact

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    ABSTRACT: The Lysine (K)-specific demethylase (LSD1) family of histone demethylases regulates chromatin structure and the transcriptional potential of genes. LSD1 is frequently deregulated in tumors and depletion of LSD1 family members causes developmental defects. Here, we report that reductions in the expression of the Pumilio (PUM) translational repressor complex enhanced phenotypes due to dLsd1 depletion in Drosophila . We show that the PUM complex is a target of LSD1 regulation in fly and mammalian cells and that its expression is inversely correlated with LSD1 levels in human bladder carcinoma. Unexpectedly, we find that PUM post-transcriptionally regulates LSD1 family protein levels in flies and human cells indicating the existence of feedback loops between the LSD1 family and the PUM complex. Our results highlight a new post-transcriptional mechanism regulating LSD1 activity and suggest that the feedback loop between LSD1 family and the PUM complex may be functionally important during development and in human malignancies.
    Molecular and Cellular Biology 09/2015; DOI:10.1128/MCB.00755-15 · 4.78 Impact Factor

  • Molecular and Cellular Biology 09/2015; · 4.78 Impact Factor
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    ABSTRACT: The retinoblastoma tumor suppressor (pRb) protein associates with chromatin and regulates gene expression. Numerous studies have identified Rb-dependent RNA signatures, but the proteomic effects of Rb loss are largely unexplored. We acutely ablated Rb in adult mice and conducted a quantitative analysis of RNA and proteomic changes in the colon and lungs, where Rb(KO) was sufficient or insufficient to induce ectopic proliferation, respectively. As expected, Rb(KO) caused similar increases in classic pRb/E2F-regulated transcripts in both tissues, but, unexpectedly, their protein products increased only in the colon, consistent with its increased proliferative index. Thus, these protein changes induced by Rb loss are coupled with proliferation but uncoupled from transcription. The proteomic changes in common between Rb(KO) tissues showed a striking decrease in proteins with mitochondrial functions. Accordingly, RB1 inactivation in human cells decreased both mitochondrial mass and oxidative phosphorylation (OXPHOS) function. RB(KO) cells showed decreased mitochondrial respiratory capacity and the accumulation of hypopolarized mitochondria. Additionally, RB/Rb loss altered mitochondrial pyruvate oxidation from (13)C-glucose through the TCA cycle in mouse tissues and cultured cells. Consequently, RB(KO) cells have an enhanced sensitivity to mitochondrial stress conditions. In summary, proteomic analyses provide a new perspective on Rb/RB1 mutation, highlighting the importance of pRb for mitochondrial function and suggesting vulnerabilities for treatment. © 2015 Nicolay et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 08/2015; 29(17). DOI:10.1101/gad.264127.115 · 10.80 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):NG08-NG08. DOI:10.1158/1538-7445.AM2015-NG08 · 9.33 Impact Factor
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    Wayne O Miles · Nicholas J Dyson ·
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    ABSTRACT: Activator E2Fs and Myc cooperate as master regulators of proliferation. A new study sheds light on one of the fundamental questions in cancer biology: how do oncogenic changes, such as Retinoblastoma (RB)-mutation, modify E2F and Myc activity?
    Nature Cell Biology 07/2015; 17(8):968-9. DOI:10.1038/ncb3213 · 19.68 Impact Factor
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    ABSTRACT: Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins-MITF, TFE3 and TFEB-are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.
    Nature 07/2015; 524(7565). DOI:10.1038/nature14587 · 41.46 Impact Factor

  • Cancer Research 07/2015; 75(13 Supplement):B42-B42. DOI:10.1158/1538-7445.PANCA2014-B42 · 9.33 Impact Factor
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    Wayne O Miles · Nicholas J Dyson ·
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    ABSTRACT: The ability of the retinoblastoma protein (RB) tumor suppressor to repress transcription stimulated by the E2 promoter binding factors (E2F) is integral to its biological functions. Our recent report described a conserved feedback mechanism mediated by the RNA-binding proteins Pumilio and Nanos that increases in importance following RB loss and helps cells to tolerate deregulated E2F.
    12/2014; 1(4):e968074. DOI:10.4161/23723548.2014.968074
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    ABSTRACT: Inactivation of the retinoblastoma tumor suppressor (pRb) is a common oncogenic event that alters the expression of genes important for cell cycle progression, senescence, and apoptosis. However, in many contexts, the properties of pRb-deficient cells are similar to wild-type cells suggesting there may be processes that counterbalance the transcriptional changes associated with pRb inactivation. Therefore, we have looked for sets of evolutionary conserved, functionally related genes that are direct targets of pRb/E2F proteins. We show that the expression of NANOS, a key facilitator of the Pumilio (PUM) post-transcriptional repressor complex, is directly repressed by pRb/E2F in flies and humans. In both species, NANOS expression increases following inactivation of pRb/RBF1 and becomes important for tissue homeostasis. By analyzing datasets from normal retinal tissue and pRb-null retinoblastomas, we find a strong enrichment for putative PUM substrates among genes de-regulated in tumors. These include pro-apoptotic genes that are transcriptionally down-regulated upon pRb loss, and we characterize two such candidates, MAP2K3 and MAP3K1, as direct PUM substrates. Our data suggest that NANOS increases in importance in pRb-deficient cells and helps to maintain homeostasis by repressing the translation of transcripts containing PUM Regulatory Elements (PRE).
    The EMBO Journal 08/2014; 33(19). DOI:10.15252/embj.201488057 · 10.43 Impact Factor
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    ABSTRACT: dREAM complexes represent the predominant form of E2F/RBF repressor complexes in Drosophila. dREAM associates with thousands of sites in the fly genome but its mechanism of action is unknown. To understand the genomic context in which dREAM acts we examined the distribution and localization of Drosophila E2F and dREAM proteins. Here we report a striking and unexpected overlap between dE2F2/dREAM sites and binding sites for the insulator-binding proteins CP190 and Beaf-32. Genetic assays show that these components functionally co-operate and chromatin immunoprecipitation experiments on mutant animals demonstrate that dE2F2 is important for association of CP190 with chromatin. dE2F2/dREAM binding sites are enriched at divergently transcribed genes, and the majority of genes upregulated by dE2F2 depletion represent the repressed half of a differentially expressed, divergently transcribed pair of genes. Analysis of mutant animals confirms that dREAM and CP190 are similarly required for transcriptional integrity at these gene pairs and suggest that dREAM functions in concert with CP190 to establish boundaries between repressed/activated genes. Consistent with the idea that dREAM co-operates with insulator-binding proteins, genomic regions bound by dREAM possess enhancer-blocking activity that depends on multiple dREAM components. These findings suggest that dREAM functions in the organization of transcriptional domains.
    Nucleic Acids Research 07/2014; 42(14). DOI:10.1093/nar/gku609 · 9.11 Impact Factor
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    ABSTRACT: Loss-of-function mutations in p16(INK4A) (CDKN2A) occur in approximately 80% of sporadic pancreatic ductal adenocarcinoma (PDAC), contributing to its early progression. Although this loss activates the cell-cycle-dependent kinases CDK4/6, which have been considered as drug targets for many years, p16(INK4A)-deficient PDAC cells are inherently resistant to CDK4/6 inhibitors. This study searched for targeted therapies that might synergize with CDK4/6 inhibition in this setting. We report that the IGF1R/IR inhibitor BMS-754807 cooperated with the CDK4/6 inhibitor PD-0332991 to strongly block proliferation of p16(INK4A)-deficient PDAC cells in vitro and in vivo. Sensitivity to this drug combination correlated with reduced activity of the master cell growth regulator mTORC1. Accordingly, replacing the IGF1R/IR inhibitor with the rapalog inhibitor temsirolimus broadened the sensitivity of PDAC cells to CDK4/6 inhibition. Our results establish targeted therapy combinations with robust cytostatic activity in p16(INK4A)-deficient PDAC cells and possible implications for improving treatment of a broad spectrum of human cancers characterized by p16(INK4A) loss. Cancer Res; 74(14); 1-12. ©2014 AACR.
    Cancer Research 07/2014; 74(14). DOI:10.1158/0008-5472.CAN-13-2923 · 9.33 Impact Factor
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    05/2014; 2(Suppl 1):O4. DOI:10.1186/2049-3002-2-S1-O4
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    ABSTRACT: Chromosome instability (CIN), a common feature of solid tumors, promotes tumor evolution and increases drug resistance during therapy. We previously demonstrated that loss of the retinoblastoma protein (pRB) tumor suppressor causes changes in centromere structure and generates CIN. However, the mechanism and significance of this change was unclear. Here, we show that defects in cohesion are key to the pRB loss phenotype. pRB loss alters H4K20 methylation, a prerequisite for efficient establishment of cohesion at centromeres. Changes in cohesin regulation are evident during S phase, where they compromise replication and increase DNA damage. Ultimately, such changes compromise mitotic fidelity following pRB loss. Remarkably, increasing cohesion suppressed all of these phenotypes and dramatically reduced CIN in cancer cells lacking functional pRB. These data explain how loss of pRB undermines genomic integrity. Given the frequent functional inactivation of pRB in cancer, conditions that increase cohesion may provide a general strategy to suppress CIN.
    Molecular cell 03/2014; 53(6). DOI:10.1016/j.molcel.2014.01.032 · 14.02 Impact Factor
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    ABSTRACT: The transition between proliferation and quiescence is frequently associated with changes in gene expression, in the extent of chromatin compaction and in histone modifications, but whether changes in chromatin state actually regulate cell cycle exit with quiescence is unclear. We discovered that primary human fibroblasts induced into quiescence exhibited tighter chromatin compaction. Mass spectrometry analysis of histone modifications revealed that H4K20me2 and -me3 are increased in quiescence and that other histone modifications are present at similar levels in proliferating and quiescent cells. Analysis of cells in S, G2/M, and G1 phases shows that H4K20me1 increases after S phase and is converted to -me2 and -me3 in quiescence. Knockdown of the enzymes that create H4K20me2 and -me3 resulted in an increased fraction of cells in S phase, a defect in exiting the cell cycle, and decreased chromatin compaction. Overexpression of Suv4-20h1, the enzyme that creates H4K20me2 from H4K20me1, resulted in G2 arrest, consistent with a role for H4K20me1 in mitosis. The results suggest that the same lysine on H4K20 may, in its different methylation states, facilitate mitotic functions in M phase and promote chromatin compaction and cell cycle exit in quiescent cells.
    Molecular biology of the cell 08/2013; 24(19). DOI:10.1091/mbc.E12-07-0529 · 4.47 Impact Factor
  • Brandon N Nicolay · Nicholas J Dyson ·
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    ABSTRACT: The pRB tumor suppressor is traditionally seen as an important regulator of the cell cycle. pRB represses the transcriptional activation of a diverse set of genes by the E2F transcription factors and prevents inappropriate S-phase entry. Advances in our understanding of pRB have documented roles that extend beyond the cell cycle and this review summarizes recent studies that link pRB to the control of cell metabolism. pRB has been shown to regulate glucose tolerance, mitogenesis, glutathione synthesis, and the expression of genes involved in central carbon metabolism. Several studies have demonstrated that pRB directly targets a set of genes that are crucial for nucleotide metabolism, and this seems likely to represent one of the ways by which pRB influences the G1/S-phase transition and S-phase progression.
    Current opinion in cell biology 08/2013; 25(6). DOI:10.1016/ · 8.47 Impact Factor
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    ABSTRACT: Acquired chromosomal instability and copy number alterations are hallmarks of cancer. Enzymes capable of promoting site-specific copy number changes have yet to be identified. Here, we demonstrate that H3K9/36me3 lysine demethylase KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability. KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase, and is not stable but is regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM, and DNA polymerase occupancy. Suv39h1/KMT1A or HP1γ overexpression suppresses the copy gain, whereas H3K9/K36 methylation interference promotes gain. Our results demonstrate that overexpression of a chromatin modifier results in site-specific copy gains. This begins to establish how copy number changes could originate during tumorigenesis and demonstrates that transient overexpression of specific chromatin modulators could promote these events.
    Cell 07/2013; 154(3). DOI:10.1016/j.cell.2013.06.051 · 32.24 Impact Factor
  • A L Manning · C Benes · N J Dyson ·
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    ABSTRACT: Whole chromosome instability (CIN) is a common feature of cancer cells and has been linked to increased tumor evolution and metastasis. Several studies have shown that the loss of the pRB tumor suppressor causes mitotic defects and chromosome mis-segregation. pRB is inactivated in many types of cancer and this raises the possibility that the loss of pRB may be a general cause of CIN in tumors. Paradoxically, retinoblastoma tumor cells have a relatively stable karyotype and currently the circumstances in which pRB inactivation causes CIN in human cancers are unclear. Here we utilize a fluorescence in situ hybridization-based approach to score numerical heterogeneity in chromosome copy number as a readout of CIN. Using this technique, we show that high levels of CIN correlate with the combined inactivation of pRB and p53 and that this association is evident in two independent panels of cancer cell lines. Retinoblastoma cell lines characteristically retain a wild-type TP53 gene, providing an opportunity to test the relevance of this functional relationship. We show that retinoblastoma cell lines display mitotic defects similar to those seen when pRB is depleted from non-transformed cells, but that the presence of wild-type p53 suppresses the accumulation of aneuploid cells. A similar synergy between pRB and p53 inactivation was observed in HCT116 cells. These results suggest that the loss of pRB promotes segregation errors, whereas loss of p53 allows tolerance and continued proliferation of the resulting, genomically unstable cancer cells. Hence, it is the cooperative effect of inactivation of both pRB and p53 tumor suppressor pathways that promotes CIN.Oncogene advance online publication, 24 June 2013; doi:10.1038/onc.2013.201.
    Oncogene 06/2013; 33(19). DOI:10.1038/onc.2013.201 · 8.46 Impact Factor
  • Luisa Di Stefano · Nicholas J Dyson ·
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    ABSTRACT: Abstract Since their discovery in 2004, histone demethylases have emerged as key regulators of chromatin. Recent studies have started to reveal the interconnections between histone demethylases and signaling pathways, suggesting that this interplay drives fundamental biological processes. Here, we summarize the different families and subfamilies of histone demethylases and the insights into the biological roles of these enzymes that have been provided by the analysis of mutant animals. We then review recent work linking demethylases and signaling pathways. These studies suggest that demethylase activities are a component of the critical connections that enable environmental signals to modulate the epigenetic landscape of a cell. A greater mechanistic understanding of the network of signals that control chromatin states during normal cellular processes, together with a better understanding of the ways that epigenetic alterations lead to uncontrolled cell proliferation, might help in the design of effective tools for cancer therapy.
    Biomolecular concepts 02/2013; 4(1):13-27. DOI:10.1515/bmc-2012-0031
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    ABSTRACT: Inactivation of the retinoblastoma tumor suppressor (pRB) alters the expression of a myriad of genes. To understand the altered cellular environment that these changes create, we took advantage of the Drosophila model system and used targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) to profile the metabolic changes that occur when RBF1, the fly ortholog of pRB, is removed. We show that RBF1-depleted tissues and larvae are sensitive to fasting. Depletion of RBF1 causes major changes in nucleotide synthesis and glutathione metabolism. Under fasting conditions, these changes interconnect, and the increased replication demand of RBF1-depleted larvae is associated with the depletion of glutathione pools. In vivo (13)C isotopic tracer analysis shows that RBF1-depleted larvae increase the flux of glutamine toward glutathione synthesis, presumably to minimize oxidative stress. Concordantly, H(2)O(2) preferentially promoted apoptosis in RBF1-depleted tissues, and the sensitivity of RBF1-depleted animals to fasting was specifically suppressed by either a glutamine supplement or the antioxidant N-acetyl-cysteine. Effects of pRB activation/inactivation on glutamine catabolism were also detected in human cell lines. These results show that the inactivation of RB proteins causes metabolic reprogramming and that these consequences of RBF/RB function are present in both flies and human cell lines.
    Genes & development 01/2013; 27(2). DOI:10.1101/gad.206227.112 · 10.80 Impact Factor
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    Jun-Yuan Ji · Wayne O Miles · Michael Korenjak · Yani Zheng · Nicholas J Dyson ·
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    ABSTRACT: The E2F transcription factors are important regulators of the cell cycle whose function is commonly misregulated in cancer. To identify novel regulators of E2F1 activity in vivo, we used Drosophila to conduct genetic screens. For this, we generated transgenic lines that allow the tissue-specific depletion of dE2F1 by RNAi. Expression of these transgenes using Gal4 drivers in the eyes and wings generated reliable and modifiable phenotypes. We then conducted genetic screens testing the capacity of Exelixis deficiencies to modify these E2F1-RNAi phenotypes. From these screens, we identified mutant alleles of Suppressor of zeste 2 [Su(z)2] and multiple Polycomb group genes as strong suppressors of the E2F1-RNA interference phenotypes. In validation of our genetic data, we find that depleting Su(z)2 in cultured Drosophila cells restores the cell-proliferation defects caused by reduction of dE2F1 by elevating the level of dE2f1. Furthermore, analyses of methylation status of histone H3 lysine 27 (H3K27me) from the published modENCODE data sets suggest that the genomic regions harboring dE2f1 gene and certain dE2f1 target genes display H3K27me during development and in several Drosophila cell lines. These in vivo observations suggest that the Polycomb group may regulate cell proliferation by repressing the transcription of dE2f1 and certain dE2F1 target genes. This mechanism may play an important role in coordinating cellular differentiation and proliferation during Drosophila development.
    G3-Genes Genomes Genetics 12/2012; 2(12):1651-60. DOI:10.1534/g3.112.004333 · 3.20 Impact Factor

Publication Stats

17k Citations
1,388.75 Total Impact Points


  • 2000-2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1996-2014
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Cell Biology
      Boston, Massachusetts, United States
  • 1992-2013
    • Massachusetts General Hospital
      • • Molecular Biology Laboratory
      • • Center for Outcomes Research (Cancer Center)
      Boston, Massachusetts, United States
  • 2009
    • Beth Israel Deaconess Medical Center
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2008
    • Universiteit Utrecht
      • Division of Developmental Biology
      Utrecht, Provincie Utrecht, Netherlands
  • 2005
    • University of Wisconsin–Madison
      • Department of Medicine
      Madison, Wisconsin, United States
  • 1991
    • Université de Sherbrooke
      Шербрук, Quebec, Canada
  • 1990
    • McMaster University
      Hamilton, Ontario, Canada
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
    • National Cancer Institute (USA)
      Maryland, United States