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Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with drug resistance in a mouse
Colin Flinders1,2, Larry Lam3, Liudmilla Rubbi3
1Department of Biological Chemistry, University of California, Los Angeles, CA, 90095, USA.
Background:
The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in drug resistance is less well understood. To investigate mechanisms of drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by drug dose escalation.
Methods:
Dose escalation of the alkylating agent mafosfamide was used to create a series of increasingly drug-resistant mouse Burkitt's lymphoma cell lines. Whole genome sequencing, DNA microarrays, reduced representation bisulfite sequencing, and chromatin immunoprecipitation sequencing were used to identify alterations in DNA sequence, mRNA expression, CpG methylation, and H3K27me3 occupancy, respectively, that were associated with increased resistance.
Results:
Our data suggest that acquired resistance cannot be explained by genetic alterations. Based on integration of transcriptional profiles with transcription factor binding data, we hypothesize that resistance is driven by epigenetic plasticity. We observed that the resistant cells had H3K27me3 and DNA methylation profiles distinct from those of the parental lines. Moreover, we observed DNA methylation changes in the promoters of genes regulated by E2a and members of the polycomb repressor complex 2 (PRC2) and differentially expressed genes were enriched for targets of E2a. The integrative analysis considering H3K27me3 further supported a role for PRC2 in mediating resistance. By integrating our results with data from the Immunological Genome Project (Immgen.org), we showed that these transcriptional changes track the B-cell maturation axis.
Conclusions:
Our data suggest a novel mechanism of drug resistance in which E2a and PRC2 drive changes in the B-cell epigenome; these alterations attenuate alkylating agent treatment-induced apoptosis.
Insights
Epigenetic plasticity, driven by E2a and polycomb repressor complex 2 (PRC2), contributes to chemotherapy drug resistance in lymphoma cells by altering gene expression and B-cell maturation. This epigenetic reprogramming bypasses genetic alterations as the sole cause of resistance.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Genetic factors are known drivers of chemotherapy resistance.
- The epigenetic contributions to drug resistance remain less understood.
- This study investigates the epigenetic mechanisms underlying drug resistance in lymphoma.
Purpose of the Study:
- To explore the role of epigenetics in acquired chemotherapy resistance.
- To identify specific epigenetic modifications and regulatory pathways involved in drug resistance.
- To investigate the relationship between epigenetic changes and B-cell maturation in the context of drug resistance.
Main Methods:
- Developed drug-resistant mouse lymphoma cell lines through mafosfamide dose escalation.
- Employed whole genome sequencing, DNA microarrays, and bisulfite sequencing to analyze genetic and epigenetic alterations.
- Utilized chromatin immunoprecipitation sequencing (ChIP-seq) to assess H3K27me3 modifications and integrated data with transcriptomic profiles.
Main Results:
- Acquired resistance was not solely explained by genetic alterations.
- Resistant cells exhibited distinct DNA methylation and H3K27me3 profiles compared to sensitive cells.
- Epigenetic plasticity, involving E2a and PRC2, was identified as a key driver of resistance, impacting gene expression and B-cell maturation axis.
Conclusions:
- A novel mechanism of drug resistance involving E2a and PRC2-mediated epigenetic changes in B cells was identified.
- These epigenetic alterations attenuate apoptosis induced by alkylating agents.
- Epigenetic reprogramming represents a significant factor in chemotherapy resistance, offering potential therapeutic targets.
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