Integrative decomposition procedure and Kappa statistics set up ATF2 ion binding module in malignant pleural mesothelioma (MPM)

Abstract

Activating transcription factor 2 (ATF2) is a member of the ATF/cyclic AMP-responsive element binding protein family of transcription factors. However, the information concerning ATF2 ion-mediated DNA binding module and function of ATF2 in malignant pleural mesothelioma (MPM) has never been addressed. In this study, by using GRNInfer and GVedit based on linear programming and a decomposition procedure, with integrated analysis of the function cluster using Kappa statistics and fuzzy heuristic clustering in MPM, we identified one ATF2 ion-mediated DNA binding module involved in invasive function including ATF2 inhibition to target genes FALZ, C20orf31, NME2, PLOD2, RNF10, and RNASEH1, upstream RNF10 and PLOD2 activation to ATF2, upstream RNASEH1 and FALZ inhibition to ATF2 from 40 MPM tumors and 5 normal pleural tissues. Remarkably, our results showed that the predominant effect of ATF2 occupancy is to suppress the activation of target genes on MPM. Importantly, the ATF2 ionmediated DNA binding module reflects ‘mutual’ positive and negative feedback regulation mechanism of ATF2 with up-and down-stream genes. It may be useful for developing novel prognostic markers and therapeutic targets in MPM.