Epstein-Barr virus (EBV), a double-stranded DNA herpesvirus, establishes a persistent infection in host cells by maintaining a chromatinized episome in the nucleus. While often asymptomatic or mild, EBV can cause life-threatening B-cell lymphomas in immunocompromised individuals, such as those with HIV or organ transplants. We recently uncovered a link between host chromatin organization and PARP1 activity in EBV-infected cells. Elevated PARP1 activity stabilizes the CTCF-Cohesin complex on DNA, and its inhibition disrupts chromatin looping, highlighting a connection between chromatin structure and cellular metabolism via NAD levels.
EBV infection enhances NAD biosynthesis in B cells by upregulating NAMPT, a key enzyme in the NAD salvage pathway. Hi-C assays revealed that NAMPT inhibition increases genome compartmentalization, driving chromatin into heterochromatic domains and disrupting chromatin loop extrusion. NAD blockade diminished long-range chromatin interactions while strengthening local ones, as shown by repositioning of Cohesin complex. Integrated Hi-C and ATAC-seq data demonstrated extensive chromatin reorganization and reduced accessibility, with RNA-seq linking these changes to genes critical for B-cell proliferation. Finally, NAMPT inhibition suppressed EBV-associated lymphoma growth in vivo.
These findings highlight the pivotal role of NAD metabolism in orchestrating chromatin architecture to drive EBV-induced B-cell proliferation
28 gennaio 2025