title: Transcript Isoform Variation Associated with Cytosine Modification in Human Lymphoblastoid Cell Lines.
abstract: Cytosine modification on DNA is variable among individuals, which could correlate with gene expression variation. The effect of cytosine modification on interindividual transcript isoform variation (TIV), however, remains unclear. In this study, we assessed the extent of cytosine modification-specific TIV in lymphoblastoid cell lines (LCLs) derived from unrelated individuals of European and African descent. Our study detected cytosine modification-specific TIVs for 17% of the analyzed genes at a 5% false discovery rate. Forty-five percent of the TIV-associated cytosine modifications correlated with the overall gene expression levels as well, with the corresponding CpG sites overrepresented in transcript initiation sites, transcription factor binding sites, and distinct histone modification peaks, suggesting that alternative isoform transcription underlies the TIVs. Our analysis also revealed 33% of the TIV-associated cytosine modifications that affected specific exons, with the corresponding CpG sites overrepresented in exon/intron junctions, splicing branching points, and transcript termination sites, implying that the TIVs are attributable to alternative splicing or transcription termination. Genetic and epigenetic regulation of TIV shared target preference but exerted independent effects on 61% of the common exon targets. Cytosine modification-specific TIVs detected from LCLs were differentially enriched in those detected from various tissues in The Cancer Genome Atlas, indicating their developmental dependency. Genes containing cytosine modification-specific TIVs were enriched in pathways of cancers and metabolic disorders. Our study demonstrated a prominent effect of cytosine modification variation on the transcript isoform spectrum over gross transcript abundance and revealed epigenetic contributions to diseases that were mediated through cytosine modification-specific TIV.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Illinois, Chicago, Illinois 60612 xuzhangchicago@gmail.com wei.zhang1@northwestern.edu.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 xuzhangchicago@gmail.com wei.zhang1@northwestern.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D017398:Alternative Splicing; D044383:Black People / Q000235:genetics; D002460:Cell Line; D018899:CpG Islands; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D020033:Protein Isoforms; D022821:RNA Splice Sites; D003596:Cytosine
keywords: DNA methylation; alternative splicing; cytosine modification; lymphoblastoid cell line; transcript isoform