title: The haploinsufficient tumor suppressor, CUX1, acts as an analog transcriptional regulator that controls target genes through distal enhancers that loop to target promoters.
abstract: One third of tumor suppressors are haploinsufficient transcriptional regulators, yet it remains unknown how a 50% reduction of a transcription factor is translated at the cis-regulatory level into a malignant transcriptional program. We studied CUX1, a haploinsufficient transcription factor that is recurrently mutated in hematopoietic and solid tumors. We determined CUX1 DNA-binding and target gene regulation in the wildtype and haploinsufficient states. CUX1 binds with transcriptional activators and cohesin at distal enhancers across three different human cell types. Haploinsufficiency of CUX1 altered the expression of a large number of genes, including cell cycle regulators, with concomitant increased cellular proliferation. Surprisingly, CUX1 occupancy decreased genome-wide in the haploinsufficient state, and binding site affinity did not correlate with differential gene expression. Instead, differentially expressed genes had multiple, low-affinity CUX1 binding sites, features of analog gene regulation. A machine-learning algorithm determined that chromatin accessibility, enhancer activity, and distance to the transcription start site are features of dose-sensitive CUX1 transcriptional regulation. Moreover, CUX1 is enriched at sites of DNA looping, as determined by Hi-C analysis, and these loops connect CUX1 to the promoters of regulated genes. We propose an analog model for haploinsufficient transcriptional deregulation mediated by higher order genome architecture.
authors.affiliation: Department of Pathology, Department of Pediatrics, Section of Hematology/Oncology, and The University of Chicago Medicine Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Arthur
authors.affiliation: Department of Pathology, Department of Pediatrics, Section of Hematology/Oncology, and The University of Chicago Medicine Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ningfei
authors.initials: N
authors.lastname: An
authors.affiliation: Department of Pathology, Department of Pediatrics, Section of Hematology/Oncology, and The University of Chicago Medicine Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Saira
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Pathology, Department of Pediatrics, Section of Hematology/Oncology, and The University of Chicago Medicine Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: McNerney
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D016384:Consensus Sequence; D004742:Enhancer Elements, Genetic; D057895:Haploinsufficiency; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D009687:Nuclear Proteins / Q000502:physiology*; D009690:Nucleic Acid Conformation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000097722:Cohesins; C080632:CUX1 protein, human