Genome-wide analysis reveals dual roles for Ikaros in regulation of macrophage chromatin state and inflammatory gene expression [RNA-seq]. Mus musculus

Macrophage activation by bacterial LPS leads to induction of a complex inflammatory gene program dependent on numerous transcription factor families. Here we describe an unexpected role for the lymphoid lineage-determining factor Ikaros in the macrophage LPS response using comprehensive genomic analysis of Ikaros-dependent transcription, DNA binding, and chromatin accessibility. Ikaros exhibited dual repressor and activator roles in LPS-induced gene expression. Consistent with the described function of Ikaros as transcriptional repressor, Ikzf1-/- cells showed enhanced induction for select responses. In contrast, we observed a dramatic defect in expression of delayed response genes and ChIP-seq analyses support a key role for Ikaros in sustained NF-kB chromatin binding. Furthermore, in the absence of Ikaros, a constitutively open chromatin state was coincident with dysregulation of LPS-induced chromatin dynamics, gene expression, and cytokine responses. Our data suggest a central role for Ikaros in coordinating the complex macrophage transcriptional program in response to pathogen challenge. Overall design: RNA-seq time course (0h, 2h, 4h, 10h) and DNase-seq time course (0h, 3h, 8h) sample replicates from WT and Ikzf KO macrophages; RelA/Ikaros ChIP-seq time course (0h, 3h, 8h) sample replicates and input control DNA samples