Immune Disease Institute
Harvard Medical School
200 Longwood Avenue., WAB
Boston, MA 02115
4 Postdoctoral Fellows, 3 Instructors, 1 Graduate Student
A major unresolved question in immunology is how specificity of gene activation is achieved after a particular cellular stress. The human tumor necrosis factor (TNF) gene provides a unique model system in which to study cell type and inducer specific transcriptional regulation, since the gene is expressed in multiple cell types stimulated through a variety of signal transduction pathways and plays an important role in many infectious and autoimmune diseases.
Studies in the lab have led to the discovery that distinct enhanceosomes form on the TNF promoter in response to different extracellular stimuli and thus they have shed light on the basic question of how eukaryotic genes are activated in a cell type- and inducer-specific manner in response to extracellular signals or infection. Recent studies in the lab have demonstrated that the regulation of TNF gene expression involves distal enhancers located over a 12 kB region that interact and form a novel double-loop chromatin configuration, which circularizes the TNF gene facilitating transcription. This study is the first demonstration of such a double looped regulatory structure in a mammalian gene. In addition, the laboratory has performed work on the evolution of the TNF gene in the primate lineage and demonstrated that different TNF promoter sequences have evolved under different constraints. The lab has discovered many novel human TNF promoter SNPs that are linked with neighboring HLA molecules in ethnic specific patterns. In recent work Dr. Goldfeld undertook the largest interspecies comparison to date of a gene’s regulatory region involved in the innate immune response.
An extension of the transcriptional studies on TNF has been to the study of transcriptional mechanisms involved in the regulation of HIV-1 transcriptional regulation via its long terminal repeat (LTR) enhancer element. HIV-1 transcription, like TNF is regulated in a cell and inducer specific manner. Using RNA silencing, the laboratory has identified novel activators of LTR activity in viral isolates from all HIV-1 viral clades tested and to the dissection of the regulation of HIV-1 replication by co-infection with tuberculosis (TB), a major focus of this work.
TB is the leading opportunistic cause of death among AIDS patients and is responsible for the loss of almost 3 million lives each year. Another major focus of the Goldfeld lab has been to understand immunological correlates with clinical outcome of TB and AIDS infections in one of the epicenters of this dual epidemic, Cambodia. Using a combination of genetic, molecular biological, and immunological approaches, Dr. Goldfeld’s laboratory has identified host susceptibility and resistance genes and their variants that influence the pathogenesis of TB and AIDS, including the identification of IL-10 producing T regulatory cells in an infectious disease, and specifically in TB. Ongoing work is focused on TB and HIV infection in the human host and genetic and immunological markers associated with clinical outcome during co-infection and treatment in Cambodia.
- Ranjbar S, Rajsbaum R, Goldfeld AE. Tat from HIV-1 subtype E differentially inhibits TNF gene expression via chromatin remodeling of the TNF locus. J. Immunol., 2006;176(7):4182-90.
- Ranjbar S, Tsytsykova AV, Lee SK, Rajsbaum R, Falvo JV, Lieberman J, Shankar P, Goldfeld AE. NFAT5 Regulates HIV-1 in Primary Monocytes via a Highly Conserved LTR Site, PLoS Pathogens, 2006 2(12):e130
- Tsytsykova AV, Falvo, JV, Schmidt-Supprian M, Courtois G, Thanos D, Goldfeld AE. Post-induction, stimulus specific regulation of TNF mRNA expression. J. Biol. Chem, 2007 Feb 15; [Epub ahead of print].
- Baena A, Falvo JV, Mootnick A, Tsytsykova AV, Ligeiro F, Diop O, O’Brien SJ, Ryder O, Goldfeld AE. Primate TNF Promoters Reveal Markers of Phylogeny and Evolution of Innate Immunity. PLoS ONE. 2007 Jul 18;2:e621.
- Tsytsykova AV, Rajsbaum R, Falvo JV, Ligeiro F, Neely SR, , Goldfeld AE. A novel activation-dependent double-loop chromatin configuration formed by the TNF gene promoter and two distal enchancers. Submitted.
Immunology webpage updated 12/02/2009