The macrophage response to LPS is marked by dynamic nucleosome positioning and increases in nucleosome sensitivity corresponding with immune regulatory factor footprints

ABSTRACT: Macrophages detect lipopolysaccharide (LPS) through toll-like receptor 4 (TLR-4) on the cell surface which initiates a signaling cascades resulting in the recruitment of regulatory factors to chromatin and subsequent expression of chemokine and cytokine genes. Primary response genes, which are marked by poised promoters and enhancers, are rapidly expressed after LPS stimulation and activate secondary response genes via paracrine and autocrine signaling pathways. While immune signaling following macrophage activation is well understood, the dynamics of nucleosome architecture and regulatory factor binding in promoter regions during early and late LPS responses remain unclear. Here, we stimulated THP-1 derived macrophages with LPS and assessed nucleosome distribution, MNase sensitivity, and small factor footprints across promoters at eight time points. We found that while nucleosome distribution was static over most promoters, LPS stimulation resulted in transient remodeling of immune and DNA repair gene promoters. We also observed distinct MNase sensitivity alterations in two phases which aligned with early/late gene expression patterns. Notably, while most Pol II promoters showed altered chromatin sensitivity, only a subset exhibited transcriptional changes, suggesting widespread chromatin remodeling uncoupled from gene expression. Small factor footprints suggested regulatory factor binding increased at promoters with altered nucleosome distributions or sensitivity, implying that nucleosome sensitivity may result from a combination of histone modifications, genome accessibility, and protein-DNA interactions. These findings provide new temporal insight into the transient and long term effects of immune stimulation on promoter architecture. This also provides a methodological framework for additional time-resolved studies of chromatin remodeling in other systems.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279622 | GEO | 2025/02/19

REPOSITORIES: GEO