A major role for the transcription factor Ikaros in sustaining the inflammatory gene program in LPS-activated macrophages

Authors

• Kyu S Oh
• RA Gottschalk
• NW Lounsbury
• Jing Sun
• SJ Baek
• B Dutta
• GL Hager
• MH Sung
• GL Hager

Abstract

The transcription factor Ikaros is an essential regulator of lymphopoiesis, and has also been shown to act as a multifunctional regulator of the transcription cycle in hematopoietic cells. Ikaros expression diminishes during differentiation of myeloid cells, so its function has been less well studied in myeloid cell types. We previously showed that Ikaros expression in macrophages is induced by LPS, it functions to promote positive feedback in NF-kappaB activation and it thus supports a robust innate transcriptional response to LPS. To gain further insight into the function and mechanisms of Ikaros action, we performed ChIP-seq, RNA-seq and DNase-seq analysis of LPS stimulated bone marrow derived macrophages from WT and Ikaros KO mice. We find that the induction of important subsets of LPS-induced genes are altered in Ikaros KO macrophages, and that LPS-induced dynamic changes in chromatin accessibility are strongly perturbed by Ikaros deficiency. Our data suggests that Ikaros has a dual role as a transcriptional repressor and activator in the LPS-induced gene program, acting predominantly as a transcriptional activator. We observe robust recruitment of Ikaros to numerous sites on macrophage chromatin in response to LPS, and a high percentage of RelA-bound NF-kappaB sites overlap with Ikaros sites, particularly at sites which show sustained binding several hours after LPS activation. We show that Ikaros and the repressive histone modifier HDAC2 co-precipitate in untreated cells, however this interaction diminishes after extended LPS treatment. We also determined that Ikaros KO cells are deficient in their response to the gram-negative bacterium B. cenocepacia.

Scientific Focus Area: Systems Biology

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