CIC (capicua transcriptional repressor)

CIC is a tissue-specific transcriptional repressor that is highly conserved between metazoan organisms and is required for the normal development of multiple adult structures. CIC functions to transduce receptor tyrosine kinase (RTK) signalling into gene expression changes through a mechanism termed default repression, wherein CIC is bound to target gene promoters or enhancers and inhibits transcription in the absence of signal. This CIC-DNA interaction can be inhibited through activation of the RTK core signalling molecule mitogen-activated protein kinase (MAPK), which then allows for the transcription of CIC targets through this RTK-MAPK signalling axis. Components of RTK signalling are commonly dysregulated in cancers, possibly implying that CIC alterations observed in specific cancer types (e.g. oligodendroglioma and Ewing-like sarcomas) are a form of RTK signalling dysregulation that drives oncogenesis. CIC is also specifically expressed in cells of the developing central nervous system and its dysfunction is associated with the neurodegenerative disorder spinocerebellar ataxia type 1, implicating CIC in neuronal cell development and/or homeostasis. Other possible cellular and physiological roles for CIC include cell cycle control, ATP-citrate lyase phosphorylation, reactive oxygen species homeostasis, and bile acid homeostasis

Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity

The majority of oligodendrogliomas (ODGs) exhibit combined losses of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH1-R132H or IDH2-R172K). Approximately 70% of ODGs with 1p19q co-deletions harbor somatic mutations in the Capicua Transcriptional Repressor (CIC) gene on chromosome 19q13.2. Here we show that endogenous long (CIC-L) and short (CIC-S) CIC proteins are predominantly localized to the nucleus or cytoplasm, respectively. Cytoplasmic CIC-S is found in close proximity to the mitochondria. To study wild type and mutant CIC function and motivated by the paucity of 1p19q co-deleted ODG lines, we created HEK293 and HOG stable cell lines ectopically co-expressing CIC and IDH1. Non-mutant lines displayed increased clonogenicity, but cells co-expressing the mutant IDH1-R132H with either CIC-S-R201W or -R1515H showed reduced clonogenicity in an additive manner, demonstrating cooperative effects in our assays. Expression of mutant CIC-R1515H increased cellular 2-Hydroxyglutarate (2HG) levels compared to wild type CIC in IDH1-R132H background. Levels of phosphorylated ATP-citrate Lyase (ACLY) were lower in cell lines expressing mutant CIC-S proteins compared to cells expressing wild type CIC-S, supporting a cytosolic citrate metabolism-related mechanism of reduced clonogenicity in our in vitro model systems. ACLY or phospho-ACLY were similarly reduced in CIC-mutant 1p19q co-deleted oligodendroglioma patient samples

Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis

The regulatory landscape of the glioma-associated transcription factor Capicua

The metazoan developmental gene capicua transcriptional repressor (CIC) encodes a transcription factor that transduces receptor tyrosine kinase signaling into gene expression changes. Aberrant CIC function is implicated in oligodendroglioma (ODG) development since one CIC allele is lost while the other is mutated in ~70% of ODGs. We therefore investigated how CIC can affect gene expression at a genome-wide level by inactivating CIC in HEK293a cells and subsequently measuring gene expression changes using microarrays. From this, gene expression changes spanning entire chromosomes were detected. Additionally, 24 candidate CIC-regulated genes were identified in HEK293a cells that also have evidence of CIC-dependent regulation in ODGs sequenced by The Cancer Genome Atlas (TCGA). Of these 24 genes, 5 genes (CNTFR, DUSP6, GPR3, SHC3, and SPRY4) with reported functions in mitogen-activated protein kinase (MAPK) signaling and central nervous system (CNS) development were further validated to undergo CIC-dependent regulation in HeLa cells. Finally, investigating how different CIC mutations affect gene expression revealed that different types of ODG-associated CIC mutations either abrogated or potentially preserved CIC’s transcriptionally repressive activity. These findings shed insight into possible roles for CIC in regulating gene expression at a chromosome-wide scale, MAPK signaling, CNS development, and ODG development.Science, Faculty ofGraduat