Thursday, November 21, 2024
11/21/2024
Epigenetics is crucial for regulating the Epstein Barr Virus (EBV) different latent gene expression programs, referred to as latency types. It has recently been discovered that these different latent programs are regulated by changes in a complex network of histone modifications, chromatin 3D structure, and epigenetic factors. However, it is still unknown what cellular signals trigger these epigenetic changes and what mechanisms couple these signals to chromatin-dependent viral gene regulation during latency. Our long-term goal is to understand how epigenetics regulates EBV latency. Cellular metabolism drives epigenetic changes as chromatin-modifying factors relay their activity on specific metabolites. Thus, metabolic changes can be coupled with transcriptional changes through epigenetic means. In the previous funding period, we identified a potential mechanism that could link NAD+ metabolism to viral EBV gene expression: PARP1 regulation of EBV chromatin; the activity of PARP1 relies on NAD+ availability. We demonstrated that: 1) EBV infection activates PARP1, and 2) PARP1 forms a complex with CTCF that controls the EBV genome 3D genome structure. Here we expand on these observations and report that in order to regulate CTCF functions and maintain an open chromatin state across the EBV genome, PARP1 may need to interact with NMNAT1. NMNAT1 is a critical nuclear enzyme for NAD+ biosynthesis in the nucleus, and an essential one for supporting PARP1 activation. We are currently confirming that NAD+ depletion alters chromatin composition and CTCF occupancy across the viral genome, eliciting cytotoxicity in EBV+ B cells. We have already identified the NuRD repressive chromatin complexes and the macroH2A1.1, a histone variant that binds NAD metabolites, as part of the mechanism that couples NAD+ levels with transcriptional changes of the EBV genome through PARP1 and CTCF. We have done this using proteomics, ChIP, and NAD+ depletion. Based on this data, we hypothesize that NAD+ metabolism influences EBV latency through PARP1-mediated chromatin changes in viral transcription programs.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
