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

Wernig-Zorc, Sara ; Yadav, Mukesh Pratap ; Kopparapu, Pradeep Kumar ; Bemark, Mats LU orcid ; Kristjansdottir, Hallgerdur Lind ; Andersson, Per Ola ; Kanduri, Chandrasekhar and Kanduri, Meena (2019) In Epigenetics and Chromatin 12. p.1-15
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... (More)

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.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
CpG islands, Enhancers and chronic lymphocytic leukemia, Hydroxymethylation
in
Epigenetics and Chromatin
volume
12
article number
4
pages
1 - 15
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85059675575
  • pmid:30616658
ISSN
1756-8935
DOI
10.1186/s13072-018-0252-7
language
English
LU publication?
no
additional info
Publisher Copyright: © 2019 The Author(s).
id
fa6f94e5-991d-4c9a-a1f0-8b9054756cb1
date added to LUP
2023-11-21 15:27:31
date last changed
2024-05-16 22:19:38
@article{fa6f94e5-991d-4c9a-a1f0-8b9054756cb1,
  abstract     = {{<p>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.</p>}},
  author       = {{Wernig-Zorc, Sara and Yadav, Mukesh Pratap and Kopparapu, Pradeep Kumar and Bemark, Mats and Kristjansdottir, Hallgerdur Lind and Andersson, Per Ola and Kanduri, Chandrasekhar and Kanduri, Meena}},
  issn         = {{1756-8935}},
  keywords     = {{CpG islands; Enhancers and chronic lymphocytic leukemia; Hydroxymethylation}},
  language     = {{eng}},
  month        = {{01}},
  pages        = {{1--15}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Epigenetics and Chromatin}},
  title        = {{Global distribution of DNA hydroxymethylation and DNA methylation in chronic lymphocytic leukemia}},
  url          = {{http://dx.doi.org/10.1186/s13072-018-0252-7}},
  doi          = {{10.1186/s13072-018-0252-7}},
  volume       = {{12}},
  year         = {{2019}},
}