Helicase Lymphoid-Specific Enzyme Contributes to the Maintenance of Methylation of SST1 Pericentromeric Repeats That Are Frequently Demethylated in Colon Cancer and Associate with Genomic Damage

DNA hypomethylation at repetitive elements accounts for the genome-wide DNA hypomethylation common in cancer, including colorectal cancer (CRC). We identified a pericentromeric repeat element called SST1 frequently hypomethylated (>5% demethylation compared with matched normal tissue) in several...

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Published in:Epigenomes 2017-06, Vol.1 (1), p.2
Main Authors: Samuelsson, Johanna K, Dumbovic, Gabrijela, Polo, Cristian, Moreta, Cristina, Alibés, Andreu, Ruiz-Larroya, Tatiana, Giménez-Bonafé, Pepita, Alonso, Sergio, Forcales, Sonia-V, Manuel, Perucho
Format: Article
Language:English
Subjects:
Aging
Azacytidine
Chromatin
Chromosomes
Colon cancer
Colorectal cancer
Colorectal carcinoma
Demethylation
Deoxyribonucleic acid
DNA
DNA damage
DNA helicase
DNA methylation
Epigenetics
Genomes
Immunoprecipitation
Lysine
p53 Protein
Tumors
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Summary:DNA hypomethylation at repetitive elements accounts for the genome-wide DNA hypomethylation common in cancer, including colorectal cancer (CRC). We identified a pericentromeric repeat element called SST1 frequently hypomethylated (>5% demethylation compared with matched normal tissue) in several cancers, including 28 of 128 (22%) CRCs. SST1 somatic demethylation associated with genome damage, especially in tumors with wild-type Seven percent of the 128 CRCs exhibited a higher ("severe") level of demethylation (≥10%) that co-occurred with mutations. SST1 demethylation correlated with distinct histone marks in CRC cell lines and primary tumors: demethylated SST1 associated with high levels of the repressive histone 3 lysine 27 trimethylation (H3K27me3) mark and lower levels of histone 3 lysine 9 trimethylation (H3K9me3). Furthermore, induced demethylation of SST1 by 5-aza-dC led to increased H3K27me3 and reduced H3K9me3. Thus, in some CRCs, SST1 demethylation reflects an epigenetic reprogramming associated with changes in chromatin structure that may affect chromosomal integrity. The chromatin remodeler factor, the helicase lymphoid-specific (HELLS) enzyme, called the "epigenetic guardian of repetitive elements", interacted with SST1 as shown by chromatin immunoprecipitation, and down-regulation of by shRNA resulted in demethylation of SST1 in vitro. Altogether these results suggest that HELLS contributes to SST1 methylation maintenance. Alterations in HELLS recruitment and function could contribute to the somatic demethylation of SST1 repeat elements undergone before and/or during CRC pathogenesis.
ISSN:2075-4655
2075-4655
DOI:10.3390/epigenomes1010002