Research Centers

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Dr. Kate Jeffrey - Epigenetic Control of Innate Immunity

Epigenetics is a general term encompassing any and all mechanisms that govern gene expression patterns without modifying the underlying DNA sequence. We are interested in how “epigenetic” mechanisms such as histone modifying enzymes and non-coding RNA regulate inflammation and antiviral immunity.

 
 

Given the continuing global burden of infectious disease, the study of host-pathogen interactions is essential for improved therapies that impact human health. We focus on understanding the role of host epigenetic programs that drive innate immune responses to pathogens, how these programs are dysregulated in disease and we how we can harness these mechanisms to boost or subdue immune responses.

The interaction of innate immune cells with pathogens leads to changes in gene expression that elicit our bodies first line of defense against infection.  These cell-lineage and signal-specific gene expression programs are primarily governed by epigenetic enzymes that regulate posttranslational modifications on histones. This 'histone code’ not only controls the accessibility of the genes to transcription factors, but also serve as docking sites for epigenetic “reader” enzymes that recruit essential transcriptional machinery. Dysregulation of these epigenetic modifiers is a recurrent and sentinel event in malignancy and inflammation. Hence, enzymes that “write”, “erase” and “read” the histone code are the most promising and intently pursued targets in drug discovery today.

While much of the histone code is set during cellular differentiation, pathogens and other environmental triggers also induce changes in the epigenetic landscape that govern gene expression programs in mature immune cells. This raises a very fundamental question of how our environment may influence immune cell behavior and gene expression in the short and long term.  

My lab currently has two active areas research: 1) Understanding the role of bromodomain-containing family of epigenetic “readers” for gene expression programs following pathogen infection of innate immune cells and 2) the contribution of small non-coding RNAs and their associated proteins to antiviral immunity.

Dr Kate L. Jeffrey is an Assistant in Immunology at Massachusetts General Hospital, Instructor of Medicine at Harvard Medical School and an associated researcher at the Broad Institute of MIT & Harvard. Kate performed her undergraduate studies at the University of Melbourne and completed her Ph.D. with Professor Charles Mackay at the Garvan Institute of Medical Research in Sydney. She then worked as an Immunology editor with Nature Medicine in New York in 2007 before performing her postdoctoral research with Professor Sasha Tarakhovsky at The Rockefeller University. Kate is also co-founder of the New York Imagine Science Film Festival, now in its 5th year in New York City.

Dr. Kate Jeffrey
Gastrointestinal Unit
Thier 3 WEL-340
Massachusetts General Hospital
60 Blossom St, Boston, MA 02114
Office: 617-643-5887
Fax: 617-724-6518
KJeffrey@mgh.harvard.edu


Stuti Mehta, Ph.D. (Postdoc)
Megha Basavappa (Research Technician)
Alex Cronkite (Research Technician)
Tim Prior (NIH NRSA Predoctoral Fellow)
Stuti Mehta, PhD (Postdoc)

Megha Basavappa (Research Technician)

Alex Cronkite (Research Technician)

Tim Prior (NIH NRSA Predoctoral Fellow)

1) We have previously shown that prevention of acetylated histone "reading" by the bromodomain and extra terminal (BET) family with a specific inhibitor markedly reduced inflammatory gene expression and inflammatory responses in vivo. There are however 46 bromodomain-containing proteins in the human genome and while the therapeutic tractability of this protein family is becoming clear, the biological characterization of these proteins, particularly in immune responses, is lacking. We are currently investigating the roles of novel bromodomain proteins in innate immunity.


2) Plants, insects and C.elegans all use non-coding RNA and RNA interference (RNAi) for silencing viral RNA. The key RNAi effector proteins, Dicer and AGO1-4, are functional in mammalian cells and execute RNAi as well as micro (mi)RNA responses for endogenous gene silencing. Whether mammalian cells still use RNAi/miRNA devices for antiviral defense remains a largely unanswered question of innate immunity. It is thought that pattern recognition receptors (PRR)s leading to the production of antiviral cytokines such as type I interferon have made RNAi mechanisms for antiviral immunity redundant. Using knockout mice and RNA sequencing technologies we are unraveling the contribution of this system to mammalian antiviral immunity.

 

 

  • Chiang HS, Zhao Y, Song JH, Liu S, Wang N, Terhorst C, Sharpe AH, Basavappa M, Jeffrey KL, Reinecker HC. GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses. Nat Immunol. 2014;15(1):63-71. PMID: 24270516.
  • Marazzi I, Ho JS, Kim J, Manicassamy B, Dewell S, Albrecht RA, Seibert CW, Schaefer U, Jeffrey KL, Prinjha RK, Lee K, Garcia-Sastre A, Roeder RG, Tarakhovsky A. Suppression of the antiviral response by an influenza histone mimic. Nature. 2012;483(7390):428-33. PMID: 22419161.
  • Nicodeme E*, Jeffrey KL*, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468(7327):1119-23. PMID: 21068722. *Contributed equally. f1000.com/7111956
  • Cheong C, Matos I, Choi JH, Dandamudi DB, Shrestha E, Longhi MP, Jeffrey KL, Anthony RM, Kluger C, Nchinda G, Koh H, Rodriguez A, Idoyaga J, Pack M, Velinzon K, Park CG, Steinman RM. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas. Cell. 2010;143(3):416-29. PMID: 21029863. f1000.com/6245956
  • Yang JS, Maurin T, Robine N, Rasmussen KD, Jeffrey KL, Chandwani R, Papapetrou EP, Sadelain M, O'Carroll D, Lai EC. Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis. Proc Natl Acad Sci U S A. 2010;107(34):15163-8. PMID: 20699384.
  • Jeffrey KL, Camps M, Rommel C, Mackay CR. Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov. 2007;6(5):391-403. PMID: 17473844.
  • Jeffrey K. Rechallenging immunological memory. Nat Med. 2007;13(10):1142. PMID: 17917658.
  • Jeffrey KL, Brummer T, Rolph MS, Liu SM, Callejas NA, Grumont RJ, Gillieron C, Mackay F, Grey S, Camps M, Rommel C, Gerondakis SD, Mackay CR. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol. 2006;7(3):274-83. PMID: 16474395. f1000.com/1031133
  • Moffatt JD, Jeffrey KL, Cocks TM. Protease-activated receptor-2 activating peptide SLIGRL inhibits bacterial lipopolysaccharide-induced recruitment of polymorphonuclear leukocytes into the airways of mice. Am J Respir Cell Mol Biol. 2002;26(6):680-4. PMID: 12034566.