TY - JOUR T1 - Combinatorial transcriptional codes specify macrophage polarization destinations JF - bioRxiv DO - 10.1101/2021.10.19.464946 SP - 2021.10.19.464946 AU - Sathyabaarathi Ravichandran AU - Bharat Bhatt AU - Kithiganahalli Narayanaswamy Balaji AU - Nagasuma Chandra Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/19/2021.10.19.464946.abstract N2 - Macrophages are driven to form distinct functional phenotypes in response to different immunological stimuli, in a process widely referred to as macrophage polarization. Transcriptional regulators that guide macrophage polarization in response to a given trigger remain largely unknown. In this study, we interrogate the programmable landscape in macrophages to find regulatory panels that determine the precise polarization state that a macrophage is driven to. Towards this, we configure an integrative network analysis pipeline that utilizes macrophage transcriptomes in response to 28 different stimuli and reconstructs contextualized human gene regulatory networks, and identifies epicentres of perturbations in each case. We find that these contextualized regulatory networks form a spectrum of thirteen distinct clusters with M1 and M2 at the two ends. Using our computational pipeline, we identify combinatorial panels of epicentric transcription factors (TFs) for each polarization state. We demonstrate that a set of three TFs i.e., NFE2L2, BCL3 and CEBPB, is sufficient to change the polarization destination from M1 to M2. siRNA-mediated knockdown of the 3-TF set in THP1 derived M0 cells, despite exposure to an M1 stimulant, significantly attenuated the shift to M1 phenotype, and instead switched to an M2-like phenotype. Further, the siRNA-mediated knockdown of the 3-TF set rendered the macrophages hyper-susceptible to S. aureus infection, clearly showing the effect of the knockdown. ER -