Recurrent gene mutations often cooperate in a predefined stepwise and synergistic manner to alter global transcription, through directly or indirectly remodeling epigenetic landscape on linear and three-dimensional (3D) scales. Here, we present a multiomics data integration approach to investigate the impact of gene mutational synergy on transcription, chromatin states, and 3D chromatin organization in a murine leukemia model. This protocol provides an executable framework to study epigenetic remodeling induced by cooperating gene mutations and to identify the critical regulatory network involved. For complete details on the use and execution of this protocol, please refer to Yun et al. (2021).