Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina–associated domains

By Benjamin Paul Berman, D. Weisenberger, Joseph F Aman, T. Hinoue, Zachary H. Ramjan, Yaping Liu, Houtan Noushmehr, Christopher P. E. Lange, C. M. van Dijk, R. Tollenaar and 2 more. Nature Genetics, 2011

668 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7331bcf10316b379c7ff5fd2355c85555df2cad9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Dynamic DNA methylation across diverse human cell lines and tissues (2013, background): “Recent reports have found that some tumors exhibit hypomethylation corresponding to lamina- associated domains (Berman et al. 2012), but we did not observe an enrichment for lamin B1 binding in the hypomethylated domains we identified.”
A Reference Methylome Database and Analysis Pipeline to Facilitate Integrative and Comparative Epigenomics (2013, background): “Comparative analysis of the methylomes of different cell types and conditions reveals functional epigenetic domains with implications in cell differentiation and disease onset [10,12,13].”
Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration (2012, background): “Colors [19], zoomed in to 75bp. CpG dinucleotides are shown as blue (unmethylated) and red (methylated) squares.”
Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules (2012, methodology): “For NOMe-seq, libraries were prepared from 5 ug of DNA as previously described (Lister et al. 2009; Kelly et al. 2010; Berman et al. 2012).”
Global Epigenomic Reconfiguration During Mammalian Brain Development (2013, background): “Given the high spatial concordance of CG PMDs and nuclear laminaassociated domains reported previously (29), the RESEARCHARTICLE”
Cancer epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance (2014, background): “These genes, when in a bivalent state, often have a low, poised level of transcription and generally switch to either an active state with predominantly promoter H3K4me3 or a repressed stat with predominantly H3K27me3 during differentiation (Bernstein et al., 2006).”
Epigenetic Determinants of Cancer. (2016, background): “…genes reside broadly correspond to late replicating and lamin-associated domains at the nuclear periphery, generally associated with repressive chromatin domains and PcG-marked, often bivalent, genes in ES cells (Peric-Hupkes and van Steensel 2010; Peric-Hupkes et al. 2010; Berman et al. 2012).”
Functional normalization of 450k methylation array data improves replication in large cancer studies (2014, background): “The global hypomethylation commonly observed in human cancers was recently shown to be organized into large, well-defined domains [9,10].”
Cancer epigenetics: from mechanism to therapy. (2012, background): “These regions appear to correlate with late-replicating regions of the genome associated with the nuclear lamina (Berman et al., 2012).”