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Epigenetics Chromatin. 2019 Jan 7;12(1):4. doi: 10.1186/s13072-018-0252-7.

Global distribution of DNA hydroxymethylation and DNA methylation in chronic lymphocytic leukemia.

Author information

1
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
2
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, 413 45, Gothenburg, Sweden.
3
Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
4
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg University, Gothenburg, Sweden.
5
Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden.
6
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, 413 45, Gothenburg, Sweden. Meena.kanduri@gu.se.

Abstract

BACKGROUND:

Chronic lymphocytic leukemia (CLL) has been a good model system to understand the functional role of 5-methylcytosine (5-mC) in cancer progression. More recently, an oxidized form of 5-mC, 5-hydroxymethylcytosine (5-hmC) has gained lot of attention as a regulatory epigenetic modification with prognostic and diagnostic implications for several cancers. However, there is no global study exploring the role of 5-hydroxymethylcytosine (5-hmC) levels in CLL. Herein, using mass spectrometry and hMeDIP-sequencing, we analysed the dynamics of 5-hmC during B cell maturation and CLL pathogenesis.

RESULTS:

We show that naïve B-cells had higher levels of 5-hmC and 5-mC compared to non-class switched and class-switched memory B-cells. We found a significant decrease in global 5-mC levels in CLL patients (n = 15) compared to naïve and memory B cells, with no changes detected between the CLL prognostic groups. On the other hand, global 5-hmC levels of CLL patients were similar to memory B cells and reduced compared to naïve B cells. Interestingly, 5-hmC levels were increased at regulatory regions such as gene-body, CpG island shores and shelves and 5-hmC distribution over the gene-body positively correlated with degree of transcriptional activity. Importantly, CLL samples showed aberrant 5-hmC and 5-mC pattern over gene-body compared to well-defined patterns in normal B-cells. Integrated analysis of 5-hmC and RNA-sequencing from CLL datasets identified three novel oncogenic drivers that could have potential roles in CLL development and progression.

CONCLUSIONS:

Thus, our study suggests that the global loss of 5-hmC, accompanied by its significant increase at the gene regulatory regions, constitute a novel hallmark of CLL pathogenesis. Our combined analysis of 5-mC and 5-hmC sequencing provided insights into the potential role of 5-hmC in modulating gene expression changes during CLL pathogenesis.

KEYWORDS:

CpG islands; Enhancers and chronic lymphocytic leukemia; Hydroxymethylation

PMID:
30616658
PMCID:
PMC6322269
DOI:
10.1186/s13072-018-0252-7
[Indexed for MEDLINE]
Free PMC Article

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