title: Effects on the transcriptome upon deletion of a distal element cannot be predicted by the size of the H3K27Ac peak in human cells.
abstract: Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with increased risk for colorectal cancer (CRC). A molecular understanding of the functional consequences of this genetic variation is complicated because most GWAS SNPs are located in non-coding regions. We used epigenomic information to identify H3K27Ac peaks in HCT116 colon cancer cells that harbor SNPs associated with an increased risk for CRC. Employing CRISPR/Cas9 nucleases, we deleted a CRC risk-associated H3K27Ac peak from HCT116 cells and observed large-scale changes in gene expression, resulting in decreased expression of many nearby genes. As a comparison, we showed that deletion of a robust H3K27Ac peak not associated with CRC had minimal effects on the transcriptome. Interestingly, although there is no H3K27Ac peak in HEK293 cells in the E7 region, deletion of this region in HEK293 cells decreased expression of several of the same genes that were downregulated in HCT116 cells, including the MYC oncogene. Accordingly, deletion of E7 causes changes in cell culture assays in HCT116 and HEK293 cells. In summary, we show that effects on the transcriptome upon deletion of a distal regulatory element cannot be predicted by the size or presence of an H3K27Ac peak.
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Yu Gyoung
authors.initials: YG
authors.lastname: Tak
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Hung
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Lijing
authors.initials: L
authors.lastname: Yao
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Grimmer
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Do
authors.affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Mital S
authors.initials: MS
authors.lastname: Bhakta
authors.affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Henriette
authors.initials: H
authors.lastname: O'Geen
authors.affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, CA 95616, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Segal
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA pfarnham@usc.edu.
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: Farnham
mesh_terms: D000107:Acetylation; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D045325:HCT116 Cells; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D050725:Papillomavirus E7 Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational; D017384:Sequence Deletion; D059467:Transcriptome
chemical_list: D006657:Histones; D050725:Papillomavirus E7 Proteins