Education

Whitehead Institute, Cambridge, MA, 09/2018

Ph.D., Biochemistry and Cell Biology, University of California, San Francisco

B.A., Molecular and Cell Biology, University of California, Berkeley

Awards and accolades

2007 - 2010 Graduate Research Felloship NSF

2013 - 2015 Stewart Trust Cancer Fellowship Alexander and Margaret Stewart Trust

2013 - 2018 Early Independence Award (DP5) NIH Office of the Director

Research Summary

We investigate the signaling pathways, transcriptional circuits, and post-transcriptional gene control mechanisms cells employ to respond to stress and maintain homeostasis. To survive environmental fluctuations such as changes in temperature, osmolarity and nutrient availability, cells have to specifically sense the perturbation and initiate an appropriate and commensurate corrective response. To meet these challenges, cells have evolved distinct stress response pathways that typically involve both fast acting post-translational mechanisms and slower gene expression programs, and these pathways adopt the architecture of negative feedback loops.

 

Over the past several years, we have taken a deep dive into one such pathway, the heat shock response, a highly conserved stress response that regulates the expression of molecular chaperones and other protein homeostasis factors. In particular, we focus on the regulation of the transcription factor Hsf1. We use budding yeast and mammalian tissue culture cells to define the quantitative control mechanisms that initiate, propagate, fine-tune and deactivate the response. To this end we combine dynamic single cell reporter assays, molecular genetics, quantitative cell biology, biochemistry, proteomics, genome-wide approaches and mathematical modeling – whatever it takes to resolve the dynamic regulatory mechanisms.

Selected Publications

Kainth AS, Chowdhary S, Pincus D, Gross DS. Primordial super-enhancers: heat shock-induced chromatin organization in yeast. Trends Cell Biol. 2021 May 14. 

Feder ZA, Ali A, Singh A, Krakowiak J, Zheng X, Bindokas VP, Wolfgeher D, Kron SJ, Pincus D. Subcellular localization of the J-protein Sis1 regulates the heat shock response. J Cell Biol. 2021 01 04; 220(1). 

Tsvetkov P, Eisen TJ, Heinrich SU, Brune Z, Hallacli E, Newby GA, Kayatekin C, Pincus D, Lindquist S. Persistent Activation of mRNA Translation by Transient Hsp90 Inhibition. Cell Rep. 2020 Sep 08; 32(10):108149. 

Tsvetkov P, Eisen TJ, Heinrich SU, Brune Z, Hallacli E, Newby GA, Kayatekin C, Pincus D, Lindquist S. Persistent Activation of mRNA Translation by Transient Hsp90 Inhibition. Cell Rep. 2020 08 11; 32(6):108001. 

Pincus D. Regulation of Hsf1 and the Heat Shock Response. Adv Exp Med Biol. 2020; 1243:41-50. 

Mace K, Krakowiak J, El-Samad H, Pincus D. Multi-kinase control of environmental stress responsive transcription. PLoS One. 2020; 15(3):e0230246. 

McCormick JW, Pincus D, Resnekov O, Reynolds KA. Strategies for Engineering and Rewiring Kinase Regulation. Trends Biochem Sci. 2020 03; 45(3):259-271.

Bushkin GG, Pincus D, Morgan JT, Richardson K, Lewis C, Chan SH, Bartel DP, Fink GR. m6A modification of a 3' UTR site reduces RME1 mRNA levels to promote meiosis. Nat Commun. 2019 07 30; 10(1):3414. 

Tye BW, Commins N, Ryazanova LV, Wühr M, Springer M, Pincus D, Churchman LS. Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness. Elife. 2019 03 07; 8. 

Chowdhary S, Kainth AS, Pincus D, Gross DS. Heat Shock Factor 1 Drives Intergenic Association of Its Target Gene Loci upon Heat Shock. Cell Rep. 2019 01 02; 26(1):18-28.e5. 

Fanning S, Haque A, Imberdis T, Baru V, Barrasa MI, Nuber S, Termine D, Ramalingam N, Ho GPH, Noble T, Sandoe J, Lou Y, Landgraf D, Freyzon Y, Newby G, Soldner F, Terry-Kantor E, Kim TE, Hofbauer HF, Becuwe M, Jaenisch R, Pincus D, Clish CB, Walther TC, Farese RV, Srinivasan S, Welte MA, Kohlwein SD, Dettmer U, Lindquist S, Selkoe D. Lipidomic Analysis of a-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Mol Cell. 2019 03 07; 73(5):1001-1014.e8. 

Pincus D, Pandey JP, Feder ZA, Creixell P, Resnekov O, Reynolds KA. Engineering allosteric regulation in protein kinases. Sci Signal. 2018 11 06; 11(555). 

Pincus D*,#, Anandhakumar J*, Thiru P, Guertin MJ, Erkine AM, Gross DS#. Genetic and epigenetic determinants establish a continuum of Hsf1 occupancy and activity across the yeast genome. Mol Biol Cell 29: 3168-82 (2018). 

Zheng X*, Beyzavi A*, Krakowiak J, Patel N, Khalil AS#, Pincus D#. Hsf1 phosphorylation generates cell-to-cell variation in Hsp90 levels and promotes phenotypic plasticity. Cell Rep 22: 3099-3106 (2018).

Krakowiak J*, Zheng X*, Patel N*, Feder ZA, Anandhakumar J, Valerius K, Gross DS#, Khalil AS#, Pincus D#. Hsf1 and Hsp70 constitute a two-component feedback loop that regulates the yeast heat shock response. eLife 7:e31668 (2018).

Zheng X*, Krakowiak J*, Patel N, Beyzavi A, Ezike J, Khalil AS#, Pincus D#. Dynamic control of Hsf1 and the heat shock response by a chaperone switch and phosphorylation. eLife 5:e18638 (2016).

Solís EJ, Pandey JP, Zheng X, Jin DX, Gupta PB, Airoldi EM, Pincus D#, Denic V#. Defining the essential function of yeast Hsf1 reveals a compact transcriptional program for maintaining eukaryotic proteostasis. Mol Cell 65: 60-71 (2016).