Studying Mechanisms of Il12b Gene Regulation by NF-κB in Macrophages

Authors

• Y Oh
• KS Oh
• MH Sung

Abstract

The interleukin(IL)-12 and IL-23 cytokines plays a pivotal role in orchestrating immune responses by bridging innate and adaptive immunity. M1-like macrophages produce these cytokines, both sharing the p40 subunit encoded by the Il12b gene. Transcriptional control of the Il12b gene is managed by the NF-kappaB (NF-κB) transcription factor family, which includes RelA, RelB, c-Rel, p50, and p52, capable of forming various homo- and heterodimer complexes. Initial studies highlight c-Rel's predominant role in Il12b induction over RelA, yet the precise regulatory mechanisms remain unclear. Understanding how c-Rel and RelA dimers bind to enhancers proximal to the Il12b gene could explain c-Rel’s regulatory function. Due to challenges in direct experimental assays, a proposed mathematical model aims to simulate Il12b gene regulation. This model integrates the actions of c-Rel and RelA dimers at enhancers proximal and distal to Il12b, enabling diverse knockout scenarios to be tested, including c-Rel or RelA knockouts and specific enhancer deletions. Additionally, to explore the functionality of putative enhancers bound by NF-κB near the Il12b gene, we extend the “Activity by Contact” (ABC) modeling framework to generate “Regulation by Contact” (RBC) models. The RBC model represents an effective framework for evaluating the frequency of enhancer-promoter interactions proximal to Il12b and assessing NF-κB binding intensity, thereby estimating how enhancers modulate IL12b responsiveness. This model enables predictions regarding which enhancers are likely to play a role in Il12b regulation. In summary, this integrated methodology offers predictive insights into novel experimental domains and innovative strategies for regulating Il12b expression.

Scientific Focus Area: Computational Biology

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