Locus-Specific Enrichment Analysis of 5-Hydroxymethylcytosine Reveals Novel Genes Associated with Breast Carcinogenesis

An imbalance in DNA methylation is a hallmark epigenetic alteration in cancer. The conversion of 5-methylcytosine (5-mC) to 5-hydroxymethyl cytosine (5-hmC), which causes the imbalance, results in aberrant gene expression. The precise functional role of 5-hydroxymethylcytosine in breast cancer remai...

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Published in:Cells (Basel, Switzerland) Switzerland), 2022-09, Vol.11 (19), p.2939
Main Authors: Ramasamy, Deepa, Rao, Arunagiri Kuha Deva Magendhra, Balaiah, Meenakumari, Vittal Rangan, Arvinden, Sundersingh, Shirley, Veluswami, Sridevi, Thangarajan, Rajkumar, Mani, Samson
Format: Article
Language:English
Subjects:
5-hydroxymethyl cytosine
Biopsy
Breast cancer
Carcinogenesis
Cytosine
Development and progression
DhMR
DMR
DNA methylation
DNA methylation or 5-methylcytosine
Epigenetics
Gene expression
Genetic aspects
Genomes
Invasiveness
methylation imbalance
Ontology
Regulatory sequences
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Summary:An imbalance in DNA methylation is a hallmark epigenetic alteration in cancer. The conversion of 5-methylcytosine (5-mC) to 5-hydroxymethyl cytosine (5-hmC), which causes the imbalance, results in aberrant gene expression. The precise functional role of 5-hydroxymethylcytosine in breast cancer remains elusive. In this study, we describe the landscape of 5-mC and 5-hmC and their association with breast cancer development. We found a distinguishable global loss of 5-hmC in the localized and invasive types of breast cancer that strongly correlate with TET expression. Genome-wide analysis revealed a unique 5-mC and 5-hmC signature in breast cancer. The differentially methylated regions (DMRs) were primarily concentrated in the proximal regulatory regions such as the promoters and UTRs, while the differentially hydroxymethylated regions (DhMRs) were densely packed in the distal regulatory regions, such as the intergenic regions (>−5 kb from TSSs). Our results indicate 4809 DMRs and 4841 DhMRs associated with breast cancer. Validation of nine 5-hmC enriched loci in a distinct set of breast cancer and normal samples positively correlated with their corresponding gene expression. The novel 5-hmC candidates such as TXNL1, and CNIH3 implicate a pro-oncogenic role in breast cancer. Overall, these results provide new insights into the loci-specific accumulation of 5-mC and 5-hmC, which are aberrantly methylated and demethylated in breast cancer.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11192939