Transcription forms and remodels supercoiling domains unfolding large-scale chromatin structures

DNA supercoiling is an inherent consequence of twisting DNA and is critical for regulating gene expression and DNA replication. However, DNA supercoiling at a genomic scale in human cells is uncharacterized. To map supercoiling we used biotinylated-trimethylpsoralen as a DNA structure probe to show the genome is organized into supercoiling domains. Domains are formed and remodeled by RNA polymerase and topoisomerase activities and are flanked by GC-AT boundaries and CTCF binding sites. Under-wound domains are transcriptionally active, enriched in topoisomerase I, “open” chromatin fibers and DNaseI sites, but are depleted of topoisomerase II. Furthermore DNA supercoiling impacts on additional levels of chromatin compaction as under-wound domains are cytologically decondensed, topologically constrained, and decompacted by transcription of short RNAs. We suggest that supercoiling domains create a topological environment that facilitates gene activation providing an evolutionary purpose for clustering genes along chromosomes

Estrogen-induced chromatin decondensation and nuclear re-organization linked to regional epigenetic regulation in breast cancer

BACKGROUND: Epigenetic changes are being increasingly recognized as a prominent feature of cancer. This occurs not only at individual genes, but also over larger chromosomal domains. To investigate this, we set out to identify large chromosomal domains of epigenetic dysregulation in breast cancers. RESULTS: We identify large regions of coordinate down-regulation of gene expression, and other regions of coordinate activation, in breast cancers and show that these regions are linked to tumor subtype. In particular we show that a group of coordinately regulated regions are expressed in luminal, estrogen-receptor positive breast tumors and cell lines. For one of these regions of coordinate gene activation, we show that regional epigenetic regulation is accompanied by visible unfolding of large-scale chromatin structure and a repositioning of the region within the nucleus. In MCF7 cells, we show that this depends on the presence of estrogen. CONCLUSIONS: Our data suggest that the liganded estrogen receptor is linked to long-range changes in higher-order chromatin organization and epigenetic dysregulation in cancer. This may suggest that as well as drugs targeting histone modifications, it will be valuable to investigate the inhibition of protein complexes involved in chromatin folding in cancer cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0719-9) contains supplementary material, which is available to authorized users

Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability

Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. Here, the authors perform genome- and epigenome-wide analyses from normal and ACC pancreatic tissue that identify aberrations in genome stability and cell cycle control