About the Jeffrey Lab
At the core of every immune response is a signal-, cell lineage-specific and kinetically precise gene expression program. It is becoming increasingly clear that the epigenome is critical for generating such precise transcriptional responses in diverse innate immune cell types. To this end, post-translational modifications on histones control the accessibility of DNA to transcription factors and serve as docking sites for epigenetic “reader” proteins that aid assembly of transcriptional machinery complexes. Dysregulation of many epigenome regulators is a recurrent and sentinel event in multiple diseases, including some immune disorders. Hence, proteins and that “write”, “erase” or “read” the epigenome are some of the most promising and intently pursued targets in drug discovery today. BET inhibitors are an exciting and novel class of epigenetic therapy that disrupt binding of “reader” proteins Brd2, Brd3 and Brd4 to modified histones. Work during my postdoctoral studies was integral to the development of these novel agents as anti-inflammatory therapies. These drugs have now entered clinical trials as novel anti-cancer and anti-inflammatory drugs. Based on this promise, my laboratory at MGH is now exploring novel epigenome reader proteins that dictate innate immune cell function. We are also investigating the potential of other small molecules targeting epigenetic machinery as a way to boost or subdue the innate immune response in disease. Furthermore, we are understanding how pathogens have hijacked the immune cell epigenome for their benefit and the consequence of mutated epigenetic enzymes for immune driven disorders.
Understanding the role of bromodomain-containing family of epigenetic “readers” for gene expression programs following pathogen infection of innate immune cells
The contribution of small non-coding RNAs and their associated proteins to antiviral immunity.
‘Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140’. Science Immunology (2017) Vol. 2, Issue 9
Epigenetic “readers” that recognize defined posttranslational modifications on histones have become desirable therapeutic targets for cancer and inflammation. SP140 is one such bromodomain- and plant homeodomain (PHD)–containing reader with immune-restricted expression, and single-nucleotide polymorphisms (SNPs) within SP140associate with Crohn’s disease (CD)…
‘Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells’. Nature Microbiology (2016) Vol. 2
Influenza A virus (IAV) causes annual epidemics and occasional pandemics, and is one of the best-characterized human RNA viral pathogens1. However, a physiologically relevant role for the RNA interference (RNAi) suppressor activity of the IAV non-structural protein 1 (NS1), reported over a decade ago2, remains unknown3. Plant and insect viruses have evolved diverse virulence proteins …
‘Beyond receptors and signaling: epigenetic factors in the regulation of innate immunity’. Immunology & Cell Biology (2015) Vol. 93, Issue 3.
The interaction of innate immune cells with pathogens leads to changes in gene expression that elicit our body’s first line of defense against infection. Although signaling pathways and transcription factors have a central role, it is becoming increasingly clear that epigenetic factors, in the form of DNA or histone modifications, as well as noncoding RNAs, are critical for generating the necessary …
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