Researcher | Research Overview
A major focus of the Goldfeld laboratory is understanding the mechanisms of transcriptional activation of the tumor necrosis factor (TNF) gene. Through studies of TNF gene expression in a range of cell types, including T cells, B cells, macrophages, and fibroblasts, the laboratory developed the paradigm of cell type- and stimulus-specific inducible eukaryotic gene regulation through the formation of distinct enhanceosomes and higher-order chromatin structure. A key feature of this process is the recruitment of different sets of transcription factors, including the nuclear factor of activated T cells (NFAT) proteins, and associated co-activators to overlapping binding motifs within a highly conserved ~200 nucleotide region of the TNF promoter. Furthermore, through comparative sequence analysis of the TNF promoter in multiple species (which was the broadest interspecies comparison for an immune response gene regulatory region) and distinct human populations, the laboratory has discovered SNPs that mark primate ancestry and that are linked with neighboring HLA molecules in ethnic-specific patterns, providing insight into the evolution of TNF gene regulation. The laboratory has also discovered that in T cells and cells of the monocyte/macrophage lineage, the native TNF locus displays distinct patterns of DNase hypersensitive sites (HSSs), which function as distal enhancers or as matrix attachment regions (MARs). In T cells, activation-dependent intrachromosomal interactions between distal enhancers and the TNF promoter bring NFAT complexes into close proximity and, through circularizing the TNF gene (the first such observation in a mammalian gene), optimally position it for transcriptional re-initiation. Ongoing work in the laboratory is elucidating the role of chromatin organization in cell type- and stimulus-specific regulation of the TNF gene, in particular during tolerance and interferon-γ stimulation. These studies have provided key insights into the basic mechanisms of inducible eukaryotic gene expression in a clinically and physiologically relevant model system.
The regulation of transcription and replication of HIV is another main research focus in the Goldfeld laboratory. Although the majority of HIV research has examined the virus in isolation, tuberculosis represents the greatest threat to AIDS patients worldwide; thus, a critical feature of studies in the laboratory is the use of co-infection model systems using both HIV and M. tuberculosis (MTb). Furthermore, by analyzing a range of viral isolates representing major HIV subtypes circulating in the world's population, the laboratory has characterized both conserved and subtype-specific sequences in the HIV long terminal repeat (LTR), identifying a role for NFAT5 as a host factor and elucidating the binding patterns of nuclear factor κB and Sp1 proteins.
A third area of focus of the Goldfeld laboratory is the study of host susceptibility and resistance genes and their variants that influence the pathogenesis of TB and AIDS, including the first identification and role of IL-10-producing T regulatory cells in an infectious disease and the first gene associated with susceptibility to TB progression. Through collaborations with international partners, the laboratory has established clinical trials with patient cohorts in Cambodia and Ethiopia. The impact of these clinical studies such as the determination of optimal timing of antiretroviral therapy in the CAMELIA (CAMbodian Early vs. Late Introduction of Antiretrovirals) trial has resulted in improved drug regimens for thousands of patients: and provides a model for HIV/TB care that will be transferred and adapted to resource-poor settings elsewhere in Asia and Africa. By nesting scientific studies within this clinical trial, the laboratory is elucidating immunological mechanisms and genetic associations with different disease outcomes in TB, AIDS, and TB/HIV co-infection.