| First Author | Daly AE | Year | 2024 |
| Journal | Genes Dev | Volume | 38 |
| Issue | 11-12 | Pages | 536-553 |
| PubMed ID | 38918046 | Mgi Jnum | J:352110 |
| Mgi Id | MGI:7704225 | Doi | 10.1101/gad.351630.124 |
| Citation | Daly AE, et al. (2024) Selective regulation of a defined subset of inflammatory and immunoregulatory genes by an NF-kappaB p50-IkappaBzeta pathway. Genes Dev 38(11-12):536-553 |
| abstractText | The five NF-kappaB family members and three nuclear IkappaB proteins play important biological roles, but the mechanisms by which distinct members of these protein families contribute to selective gene transcription remain poorly understood, especially at a genome-wide scale. Using nascent transcript RNA-seq, we observed considerable overlap between p50-dependent and IkappaBzeta-dependent genes in Toll-like receptor 4 (TLR4)-activated macrophages. Key immunoregulatory genes, including Il6, Il1b, Nos2, Lcn2, and Batf, are among the p50-IkappaBzeta-codependent genes. IkappaBzeta-bound genomic sites are occupied at earlier time points by NF-kappaB dimers. However, p50-IkappaBzeta codependence does not coincide with preferential binding of either p50 or IkappaBzeta, as RelA co-occupies hundreds of genomic sites with the two proteins. A common feature of p50-IkappaBzeta-codependent genes is a nearby p50/RelA/IkappaBzeta-cobound site exhibiting p50-dependent binding of both RelA and IkappaBzeta. This and other results suggest that IkappaBzeta acts in concert with RelA:p50 heterodimers. Notably, p50-IkappaBzeta-codependent genes comprise a high percentage of genes exhibiting the greatest differential expression between TLR4-stimulated and tumor necrosis factor receptor (TNFR)-stimulated macrophages. Thus, our genome-centric analysis reveals a defined p50-IkappaBzeta pathway that selectively activates a set of key immunoregulatory genes and serves as an important contributor to differential TNFR and TLR4 responses. |
