Photo of Nicholas J. Dyson,  PhD

Nicholas J. Dyson, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 726-7804
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

The Dyson Laboratory studies the role of the retinoblastoma tumor suppressor (pRB). pRB is expressed in most cell types and its functions enable cells to stop dividing. pRB is inactivated in many types of cancer; a change that is thought to be an important step in tumor progression. We have three main goals: we want to understand the molecular details of how pRB acts, we want to know how the inactivation of pRB changes the cell, and we are using these insights to target tumor cells.

My group investigates the mechanisms that limit cell proliferation in normal cells and the ways that these controls are eroded in cancer cells. Our research focuses on the protein product of the retinoblastoma susceptibility gene (RB1) and its target, the E2F transcription factor. E2F controls the expression of a large number of target genes that are needed for cell proliferation. This transcriptional program is activated when normal cells are instructed to divide, but it is deregulated in tumor cells, providing a cellular environment that is permissive for uncontrolled proliferation. pRB has multiple activities but one of its most important roles is to limit the transcription of E2F targets. As a result, most tumor cells select for changes that compromise pRB function. Our current research program spans four different aspects of pRB/E2F biology.

a. Dissecting the molecular functions of pRB

pRB’s mechanism of action is an enigma. Ironically, this is not because little is known; instead pRB has been linked to hundreds of proteins and implicated in many cellular processes, and this has created a confusing picture. Currently, the major issues are: which of pRB’s activities and interactions are functionally important, how are all of these activities regulated, and how is the pool of pRB divided been all of its potential targets?

A key technical obstacle that has prevented resolution of these issues is that it has not yet been possible to purify endogenous pRB complexes from human cells and to profile the components. Because of this, it has been unclear precisely which proteins are targeted by pRB at any given moment. Very recently, we have solved this problem. We are now able to isolate the endogenous pRB complexes from normal cells and, in collaboration with the Haas lab we are using Mass Spectrometry to obtain detailed snapshots of pRB in action. In addition, we have taken advantage of an shRNA resource at the MGH Cancer Center and have built a library of constructs that target each of the 230 proteins that have been reported to physically interact with pRB. Together, these tools give us a great opportunity to identify the proteins that interact with pRB and to dissect the processes that are the molecular basis for pRB function.

b. Proteomic profiles give a new perspective on the effects of RB1 mutation

The activity of pRB, and changes in E2F regulation have traditionally been measured by quantifying the levels of RNA transcripts synthesized from genes that are directly controlled by pRB/E2F proteins. pRB inactivation changes the transcription of a vast number of genes (between hundreds and thousands) and it has not been feasible to ask whether most of these changes in mRNA levels affect protein levels. For over two decades it has been assumed that the changes in levels of RNA transcripts in RB1 mutant cells are generally followed by similar changes in protein synthesis; and that the RNA signatures associated with pRBB loss/E2F activation give us a meaningful picture of the consequences of RB1 inactivatedmutation.

Taking advantage of the latest developments in quantitative proteomics we have been able to move beyond this stumbling block. We generated proteomic profiles of tissues shortly after ablation of the mouse Rb1 gene. Remarkably, when the protein changes were compared with the changes detected by RNA-sequencing we discovered that the two types of profiles give strikingly different answers. This new data shows that mutation of Rb1 has effects on protein levels that are very different from, and far more extensive than, the changes predicted from RNA data. Taken together results indicate that the transcripts upregulated by Rb1/RB1 loss are subject to extensive post-transcriptional control. This mechanism of regulation is not well understood but is clearly an important aspect of E2F biology.

One of the surprising features of the proteomic data is that the most consistent change in different Rb1 mutant tissues is a decrease in mitochondrial proteins. Accordingly we discovered that RB1 mutant cells have a proliferation disadvantage when they are grown in low-glucose conditions that put extra demands on mitochondrial function. In such conditions, pRB-deficient cells are more sensitive to mitochondrial poisons. These results are exciting because they show that the mutation of Rb1/RB1 changes the cell in ways that had not previously been suspected. The protein signatures may provide useful biomarkers in tumor samples and, most importantly, they may reveal new ways to target tumor cells.

c. Targeting tumor cells with RB1 mutations.

The ultimate goal of all RB research is to use the information gleaned from molecular and mechanistic studies to improve cancer treatments. The activity of pRB can be altered in several different ways and pRB is functionally compromised in most types of cancer. However, in three types of tumor (retinoblastoma, osteosarcoma and small cell lung cancer) RB1 is almost always mutated. We infer from this that the complete elimination of pRB activity is especially significant in these tumors.

We have compiled a list of changes that may represent vulnerabilities that can be targeted in RB1 mutant tumors. This analysis has been greatly enhanced by a collaboration with the Broad Institute that has enabled us to examine the results of high-throughput screens that have systematically profiled cancer cell lines for shRNAs that affect cell proliferation. By classifying the cell lines according by their RB1 status we have identified proteins that are more important for the proliferation of RB1 mutant cells than other cells. Our results suggest that there may not be a single weakness that is universal to all RB1 mutant cancers, but that different types of RB1 mutant tumors need to be targeted in specific ways. Perhaps most importantly, we now have well-justified lists of candidate genes to assay in different types of RB1 mutant tumors.

d. The biological consequences of eliminating E2F activity.

The deregulation of E2F is an important consequence of pRB-inactivation and inhibition of E2F activity has been widely discussed as a potential therapeutic strategy. To understand the consequences of global inhibition of E2F activity we have taken advantage of the relative simplicity of the Drosophila E2F/RB network and are carrying out a detailed analysis of dDP mutant animals, in which loss of dDP eliminates E2F function. dDP mutation causes extensive transcriptional changes. Proteomic profiles of dDP mutant animals reveal changes in protein levels that are different from, and even more extensive than, the transcriptional changes. By integrating the RNA and protein profiles with ChIP data showing the genome-wide distribution of E2F and RBF proteins, we have identified a small set of direct dE2F/dDP target genes that display strong changes in both RNA and protein levels in dDP mutant tissues. These candidates are currently being tested in genetic studies to identify the direct targets of dE2F/dDP proteins that are functionally significant drivers of dDP mutant phenotypes.


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  • Sanidas I, Dyson NJ. pRB Takes an EZ Path to a Repetitive Task. Mol Cell 2016; 64:1015-1017. PubMed
  • Kottakis F, Nicolay BN, Roumane A, Karnik R, Gu H, Nagle JM, Boukhali M, Hayward MC, Li YY, Chen T, Liesa M, Hammerman PS, Wong KK, Hayes DN, Shirihai OS, Dyson NJ, Haas W, Meissner A, Bardeesy N. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 2016; 539:390-395. PubMed
  • Miles WO, Lepesant JM, Bourdeaux J, Texier M, Kerenyi MA, Nakakido M, Hamamoto R, Orkin SH, Dyson NJ, Di Stefano L. The LSD1 Family of Histone Demethylases and the Pumilio Posttranscriptional Repressor Function in a Complex Regulatory Feedback Loop. Mol Cell Biol 2015; 35:4199-211. PubMed
  • Denechaud PD, Lopez-Mejia IC, Giralt A, Lai Q, Blanchet E, Delacuisine B, Nicolay BN, Dyson NJ, Bonner C, Pattou F, Annicotte JS, Fajas L. E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis. J Clin Invest 2015. PubMed
  • 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
  • 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
  • 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
  • Heilmann AM, Dyson NJ. Phosphorylation puts the pRb tumor suppressor into shape. Genes Dev 2012; 26:1128-30. PubMed
  • Nicolay BN, Dyson NJ. It's all in the timing: too much E2F is a bad thing. PLoS Genet. 2012; 8:e1002909. 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,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
  • Moon NS, Dyson N. E2F7 and E2F8 keep the E2F family in balance. Dev Cell 2008; 14:1-3. 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