NFκB dynamics-dependent epigenetic changes modulate inflammatory gene expression and induce cellular senescence

• Published in: The FEBS journal
• Main Authors: Tabata, Sho, Matsuda, Keita, Soeda, Shou, Nagai, Kenshiro, Izumi, Yoshihiro, Takahashi, Masatomo, Motomura, Yasutaka, Ichikawa Nagasato, Ayaka, Moro, Kazuyo, Bamba, Takeshi, Okada, Mariko
• Format: Journal Article
• Language: English
• Published: England 16.07.2024
• Subjects: nuclear dynamics; cellular senescence; NFκB; SASP; inflammatory aging
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.17227

Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age-related chronic inflammation. However, its effect on cellular senescence remains unclear. Here, we show that alteration of NFκB nuclear dynamics from oscillatory to sustained by depleting a negative feedback regulator of NFκB pathway, NFκB inhibitor alpha (IκBα), in the presence of tumor necrosis factor α (TNFα) promotes cellular senescence. Sustained NFκB activity enhanced inflammatory gene expression through increased NFκB-DNA binding and slowed the cell cycle. IκBα protein was decreased under replicative or oxidative stress in vitro. Furthermore, a decrease in IκBα protein and an increase in DNA-NFκB binding at the transcription start sites of age-associated genes in aged mouse hearts suggested that nuclear NFκB dynamics may play a critical role in the progression of aging. Our study suggests that nuclear NFκB dynamics-dependent epigenetic changes regulated over time in a living system, possibly through a decrease in IκBα, enhance the expression of inflammatory genes to advance the cells to a senescent state.