Multi-omic analyses reveal a role for mammalian CIC in cell cycle regulation and mitotic fidelity

CIC encodes a transcriptional repressor that is inactivated by loss-of-function mutations in several cancer types, indicating that it may function as a tumor suppressor. Recent studies have indicated that CIC may regulate cell cycle genes in humans; however, a systematic investigation of this proposed role has not yet been reported. Here, we used single-cell RNA sequencing to show that inactivation of CIC in human cell lines correlated with transcriptional dysregulation of genes involved in cell cycle control. We also mapped CIC’s protein-protein and genetic interaction networks, identifying interactions between CIC and members of the Switch/Sucrose Non-Fermenting (SWI/SNF) complex as well as revealing novel candidate interactions between CIC and cell cycle regulators. We further showed that CIC loss was associated with an increased frequency of mitotic defects in human cell lines and in a mouse model. Our study thus positions CIC as a cell cycle regulator and indicates that CIC loss can lead to mitotic errors, consistent with CIC’s emerging role as a tumor suppressor of relevance in several cancer contexts.