title: Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains.
abstract: Extensive changes in DNA methylation are common in cancer and may contribute to oncogenesis through transcriptional silencing of tumor-suppressor genes. Genome-scale studies have yielded important insights into these changes but have focused on CpG islands or gene promoters. We used whole-genome bisulfite sequencing (bisulfite-seq) to comprehensively profile a primary human colorectal tumor and adjacent normal colon tissue at single-basepair resolution. Regions of focal hypermethylation in the tumor were located primarily at CpG islands and were concentrated within regions of long-range (>100 kb) hypomethylation. These hypomethylated domains covered nearly half of the genome and coincided with late replication and attachment to the nuclear lamina in human cell lines. We confirmed the confluence of hypermethylation and hypomethylation within these domains in 25 diverse colorectal tumors and matched adjacent tissue. We propose that widespread DNA methylation changes in cancer are linked to silencing programs orchestrated by the three-dimensional organization of chromatin within the nucleus.
authors: University of Southern California Epigenome Center, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.
authors: Benjamin P
authors: BP
authors: Berman
authors: Daniel J
authors: DJ
authors: Weisenberger
authors: Joseph F
authors: JF
authors: Aman
authors: Toshinori
authors: T
authors: Hinoue
authors: Zachary
authors: Z
authors: Ramjan
authors: Yaping
authors: Y
authors: Liu
authors: Houtan
authors: H
authors: Noushmehr
authors: Christopher P E
authors: CP
authors: Lange
authors: Cornelis M
authors: CM
authors: van Dijk
authors: Rob A E M
authors: RA
authors: Tollenaar
authors: David
authors: D
authors: Van Den Berg
authors: Peter W
authors: PW
authors: Laird
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D003106:Colon; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm; D020868:Gene Silencing; D015894:Genome, Human; D006801:Humans; D034881:Nuclear Lamina / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004273:DNA, Neoplasm