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Genome Biol. 2016 Jan 26;17:11. doi: 10.1186/s13059-016-0879-2.

Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer.

Author information

1
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. hheyn@idibell.cat.
2
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. evidalo@idibell.cat.
3
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. hferreira@idibell.cat.
4
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. mvizoso@idibell.cat.
5
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. S.SayolsPuig@imb-mainz.de.
6
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. antgomo@gmail.com.
7
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. smoran@idibell.cat.
8
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. rboque@idibell.cat.
9
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. sguil@idibell.cat.
10
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. amartinezc@idibell.cat.
11
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA. charles_lin@dfci.harvard.edu.
12
Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. charles_lin@dfci.harvard.edu.
13
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA, 02115, USA. charles_lin@dfci.harvard.edu.
14
Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Program in Computational Biology, Baldiri Reixac 10-12, 08028, Barcelona, Catalonia, Spain. rroyo@bsc.es.
15
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. jose.sanchezmut@epfl.ch.
16
Department of Neurosurgery, University of Goettingen, Robert Koch. Str. 40, 37075, Goettingen, Germany. ramon.martinez@med.uni-goettingen.de.
17
Centre Nacional d'Anàlisi Genòmica, Barcelona, Catalonia, Spain. marta.gut@cnag.crg.eu.
18
Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Program in Computational Biology, Baldiri Reixac 10-12, 08028, Barcelona, Catalonia, Spain. david.torrents@bsc.es.
19
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Catalonia, Spain. david.torrents@bsc.es.
20
Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Program in Computational Biology, Baldiri Reixac 10-12, 08028, Barcelona, Catalonia, Spain. modesto.orozco@irbbarcelona.org.
21
Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10-12, 08028, Barcelona, Catalonia, Spain. modesto.orozco@irbbarcelona.org.
22
Department of Biochemistry and Molecular Biology, University of Barcelona, 08028, Barcelona, Catalonia, Spain. modesto.orozco@irbbarcelona.org.
23
Centre Nacional d'Anàlisi Genòmica, Barcelona, Catalonia, Spain. ivo.gut@cnag.crg.eu.
24
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA. young@wi.mit.edu.
25
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. young@wi.mit.edu.
26
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. mesteller@idibell.cat.
27
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Catalonia, Spain. mesteller@idibell.cat.
28
Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain. mesteller@idibell.cat.

Abstract

BACKGROUND:

One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized.

RESULTS:

Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis.

CONCLUSIONS:

We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes.

PMID:
26813288
PMCID:
PMC4728783
DOI:
10.1186/s13059-016-0879-2
[Indexed for MEDLINE]
Free PMC Article

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