Characterizing the dynamics and cell state specificity of DNA methylation and demethylation at the BRCA1 promoter

Daisy Lockshire

Document Type

Article

Publication Date

8-9-2024

Keywords

JGM

JAX Location

In: Student Reports, Summer 2024, The Jackson Laboratory

Abstract

Triple-negative breast cancer (TNBC) remains a formidable health challenge, particularly for historically understudied populations such as Black women in the United States, in which individuals are at a three-fold risk of developing this aggressive subtype, and 30% more likely to succumb to its effects, compared to non-Hispanic white women with the same diagnosis. In a 2022 study Menghi et al. investigated a mechanism for chemotherapy resistance in TNBC with homologous recombination deficiency (HRD) uncovering the integral role of reversible BRCA1 promoter hypermethylation in platinum-based therapy resistance. Here, we report on the dynamics and cell state specificity of both the gain and loss of BRCA1 promoter methylation in a 353 bp region in the core promoter region, the only differentially methylated region between BRCA1 mutated versus BRCA1 methylated cancer genomes.

Utilizing a unique model system that induces methylation in cis in induced pluripotent stem cell lines (iPSCs) but not in transformed cell lines, we noted that methylation occurs in a processive manner from the 3’ untranslated region (UTR) and stabilizes at a heterozygous state at approximately 100 days.

Employing patient-derived xenograft (PDX) mouse models treated with regiments of chemotherapeutic agents and a noteworthy longitudinal series from a patient who underwent treatment we account for a significant pattern of demethylation at CpG sites in the promoter region that may correlate with BRCA1 re-expression that accounts for enhanced DNA repair and adaptative resistance to therapies in the clinical setting.

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