Photo of Nicholas J. Dyson,  PhD

Nicholas J. Dyson, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 724-9888
Fax: (617) 726-7808

Nicholas J. Dyson, PhD

Massachusetts General Hospital


  • Professor, Medicine, Harvard Medical School
  • Member, MGH Cancer Center, Massachusetts General Hospital


Research Abstract

We study the functions of the E2F transcription factor and retinoblastoma (RB) family of proteins, two groups of proteins that are important regulators of cell proliferation. During G1 to S phase progression, the activation of cyclin dependent kinases in G1 leads to the phosphorylation of RB-family proteins (pRB, p107 and p130), and the activation of the E2F-dependent transcription. E2F co-ordinates the expression of a set of genes that encode proteins that are essential for DNA synthesis. This series of events is tightly controlled in normal cells but is deregulated in most, if not all, tumor cells. Viral oncoproteins such as Adenovirus E1A, SV40 large T antigen and E7 proteins of human papillomaviruses have evolved to target RB-family proteins and the viruses exploit these interactions to drive quiescent cells into the cell cycle.

We use a combination of genetic and biochemical approaches to study E2F and RB-family proteins. A major goal is to identify the individual functions of RB-family proteins in the regulation of E2F activity. Because the overexpression of closely related family members often leads to a loss of specificity, our recent efforts have concentrated on loss-of-function approaches. Using primary cells from knockout mice that lack various family members, we have identified E2F-target genes that require either pRB or p107/p130 for their normal patterns of expression and have begun to identify elements of cell cycle control that depend on either pRB, p107 or p130.

To investigate the pathways that converge on E2F and the RB-family we have identified and characterized homologs of E2F (dE2F, dDP) and the RB-family (RBF) in Drosophila. We found that the Drosophila proteins control cell proliferation in ways that are directly analogous to their mammalian counterparts. We have two major goals that exploit the advantages of Drosophila. First, in order to identify the pathways that interact with E2F and RBF, we have set up genetic screens for mutations that modify dE2F/dDP- and RBF-dependent phenotypes. These phenotypes have been generated in transgenic lines by elevating the expression of dE2F, dDP and RBF specifically in the eye. Second, we are characterizing the phenotypes of mutant alleles of dE2F and RBF. Not surprisingly, these mutants have phenotypes that are far more severe than mutations of individual E2F or RB-family members in mice, and are likely to give insight into the general roles of these groups of proteins.


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  • Nicolay BN, Danielian PS, Kottakis F, Lapek JD, Sanidas I, Miles WO, Dehnad M, Tschöp K, Gierut JJ, Manning AL, Morris R, Haigis K, Bardeesy N, Lees JA, Haas W, Dyson NJ. Proteomic analysis of pRb loss highlights a signature of decreased mitochondrial oxidative phosphorylation. Genes Dev 2015; 29:1875-89. PubMed
  • Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, Lengrand J, Deshpande V, Selig MK, Ferrone CR, Settleman J, Stephanopoulos G, Dyson NJ, Zoncu R, Ramaswamy S, Haas W, Bardeesy N. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 2015. PubMed
  • Miles WO, Korenjak M, Griffiths LM, Dyer MA, Provero P, Dyson NJ. Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells. EMBO J 2014. PubMed
  • Korenjak M, Kwon E, Morris RT, Anderssen E, Amzallag A, Ramaswamy S, Dyson NJ. dREAM co-operates with insulator-binding proteins and regulates expression at divergently paired genes. Nucleic Acids Res 2014. PubMed
  • Heilmann AM, Perera RM, Ecker V, Nicolay BN, Bardeesy N, Benes CH, Dyson NJ. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res 2014; 74:3947-58. PubMed
  • Manning AL, Yazinski SA, Nicolay B, Bryll A, Zou L, Dyson NJ. Suppression of genome instability in pRB-deficient cells by enhancement of chromosome cohesion. Mol Cell 2014; 53:993-1004. PubMed
  • Evertts AG, Manning AL, Wang X, Dyson NJ, Garcia BA, Coller HA. H4K20 methylation regulates quiescence and chromatin compaction. Mol Biol Cell 2013; 24:3025-37. PubMed
  • Black JC, Manning AL, Van Rechem C, Kim J, Ladd B, Cho J, Pineda CM, Murphy N, Daniels DL, Montagna C, Lewis PW, Glass K, Allis CD, Dyson NJ, Getz G, Whetstine JR. KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell 2013; 154:541-55. PubMed
  • Nicolay BN, Gameiro PA, Tschöp K, Korenjak M, Heilmann AM, Asara JM, Stephanopoulos G, Iliopoulos O, Dyson NJ. Loss of RBF1 changes glutamine catabolism. Genes Dev 2013; 27:182-96. PubMed
  • Ji JY, Miles WO, Korenjak M, Zheng Y, Dyson NJ. In vivo regulation of E2F1 by Polycomb group genes in Drosophila. 2012; 2:1651-60. PubMed
  • Korenjak M, Anderssen E, Ramaswamy S, Whetstine JR, Dyson NJ. RBF Binding to both Canonical E2F Targets and Noncanonical Targets Depends on Functional dE2F/dDP Complexes. Mol Cell Biol 2012; 32:4375-87. PubMed
  • Herr A, Longworth M, Ji JY, Korenjak M, Macalpine DM, Dyson NJ. Identification of E2F target genes that are rate limiting for dE2F1-dependent cell proliferation. Dev Dyn 2012; 241:1695-707. PubMed
  • Nicolay BN, Dyson NJ. It's all in the timing: too much E2F is a bad thing. PLoS Genet. 2012; 8:e1002909. PubMed
  • Heilmann AM, Dyson NJ. Phosphorylation puts the pRb tumor suppressor into shape. Genes Dev 2012; 26:1128-30. PubMed
  • Di Stefano L, Walker JA, Burgio G, Corona DF, Mulligan P, Näär AM, Dyson NJ. Functional antagonism between histone H3K4 demethylases in vivo. Genes Dev 2011; 25:17-28. PubMed
  • Black JC, Allen A, Van Rechem C, Forbes E, Longworth M, Tschöp K, Rinehart C, Quiton J, Walsh R, Smallwood A, Dyson NJ, Whetstine JR. Conserved antagonism between JMJD2A/KDM4A and HP1粒 during cell cycle progression. Mol Cell 2010; 40:736-48. PubMed
  • Centore RC, Havens CG, Manning AL, Li JM, Flynn RL, Tse A, Jin J, Dyson NJ, Walter JC, Zou L. CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Mol Cell 2010; 40:22-33. PubMed
  • Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, Boss O, Hirsch ML, Ribich S, Smith JJ, Israelian K, Westphal CH, Rodgers JT, Shioda T, Elson SL, Mulligan P, Najafi-Shoushtari H, Black JC, Thakur JK, Kadyk LC, Whetstine JR, Mostoslavsky R, Puigserver P, Li X, Dyson NJ, Hart AC, Näär AM. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev 2010; 24:1403-17. PubMed
  • Manning AL, Longworth MS, Dyson NJ. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev 2010; 24:1364-76. PubMed
  • Longworth MS, Dyson NJ. pRb, a local chromatin organizer with global possibilities. Chromosoma 2010; 119:1-11. PubMed
  • Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 2009; 11:1444-50. PubMed
  • Morris EJ,Ji JY,Yang F,Di Stefano L,Herr A,Moon NS,Kwon EJ,Haigis KM,Naar AM,Dyson NJ. E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 2008; 455:552-6. PubMed
  • van den Heuvel S,Dyson NJ. Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 2008; 9:713-24. PubMed
  • Longworth MS, Herr A, Ji JY, Dyson NJ. RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Genes Dev 2008; 22:1011-24. PubMed
  • Wu X, Yamada-Mabuchi M, Morris EJ, Tanwar PS, Dobens L, Gluderer S, Khan S, Cao J, Stocker H, Hafen E, Dyson NJ, Raftery LA. The Drosophila homolog of human tumor suppressor TSC-22 promotes cellular growth, proliferation, and survival. Proc Natl Acad Sci U S A 2008; 105:5414-9. PubMed
  • Moon NS, Dyson N. E2F7 and E2F8 keep the E2F family in balance. Dev Cell 2008; 14:1-3. PubMed
  • Moon NS,Di Stefano L,Morris EJ,Patel R,White K,Dyson NJ. E2F and p53 induce apoptosis independently during Drosophila development but intersect in the context of DNA damage. PLoS Genet 2008; 4:e1000153. PubMed
  • Isaac CE, Francis SM, Martens AL, Julian LM, Seifried LA, Erdmann N, Binn. The retinoblastoma protein regulates pericentric heterochromatin. Mol Cell Biol 2006; 26:3659-71. PubMed
  • Moon NS, Frolov MV, Kwon EJ, Di Stefano L, Dimova DK, Morris EJ, Taylor-Harding B, White K, Dyson NJ. Drosophila E2F1 has context-specific pro- and antiapoptotic properties during development. Dev Cell 2005; 9:463-75. PubMed