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. 2024 Nov;291(22):4951-4968.
doi: 10.1111/febs.17227. Epub 2024 Jul 16.

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

Sho Tabata  1 , Keita Matsuda  1 , Shou Soeda  1 , Kenshiro Nagai  1 , Yoshihiro Izumi  2 , Masatomo Takahashi  2 , Yasutaka Motomura  3   4   5 , Ayaka Ichikawa Nagasato  1 , Kazuyo Moro  3   4   5   6 , Takeshi Bamba  2 , Mariko Okada  1   7
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Free article

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

Sho Tabata et al. FEBS J. 2024 Nov.
Free article

Abstract

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.

Keywords: NFκB; SASP; cellular senescence; inflammatory aging; nuclear dynamics.

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