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Correlating Gene-specific DNA Methylation Changes with Expression and Transcriptional Activity of Astrocytic KCNJ10 Kir4.1
Published on: September 26, 2015
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Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia
Yu-Ling Chang1, Maura Rossetti1, David W Gjertson1,2
1Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Summary
Antibiotic persistence in Staphylococcus aureus bacteremia is linked to distinct DNA methylation patterns in immune cells. These epigenetic differences, particularly in neutrophils, can help predict persistent infections despite antibiotic treatment.
Area of Science:
- Genomics
- Immunology
- Infectious Diseases
Background:
- Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia poses a life-threatening risk, occurring in up to 30% of cases despite treatment.
- Antibiotic-persistent MRSA bacteremia (APMB) isolates show similar in vitro susceptibility to antibiotic-resolving MRSA bacteremia (ARMB) isolates, indicating host-pathogen interactions in vivo are key.
- The host factors and mechanisms driving APMB remain poorly understood.
Purpose of the Study:
- To compare DNA methylomes in circulating immune cells from patients with APMB versus ARMB.
- To identify distinct epigenetic signatures associated with antibiotic persistence in MRSA bacteremia.
- To explore the potential of these epigenetic signatures for risk stratification.
Main Methods:
- DNA methylomes of circulating immune cells from APMB and ARMB patient cohorts were compared using genome-wide methylation analysis.
- Differentially methylated sites were analyzed for proximity to transcription factor binding sites, particularly in enhancer regions.
- A classification model was developed using methylation signatures to predict APMB, validated by targeted bisulfite sequencing (TBS-seq).
Main Results:
- Significant divergence in methylation signatures was observed between APMB and ARMB patient cohorts.
- APMB patients showed hypomethylation at binding sites for C/EBPβ and STAT1, while ARMB patients exhibited hypomethylation at glucocorticoid receptor and p300 binding sites.
- Distinct methylation signatures, enriched in neutrophils, achieved an AUC of 0.85 in predicting APMB.
Conclusions:
- Epigenetic profiling of immune cells differentiates patients with APMB from those with ARMB.
- Specific DNA methylation patterns, particularly involving C/EBPβ and STAT1, are associated with antibiotic persistence in MRSA bacteremia.
- These findings suggest a potential epigenetic-based risk stratification strategy for patients with MRSA bacteremia.
