37. Cell-type-specific genetic-to-epigenetic relationships in the human breast

Aly Abdelkareem

Axel Hauduc

Axel Hauduc is a Ph.D. candidate in the Hirst Lab at the University of British Columbia, Canada. Axel grew up in the Seattle area and attended the University of California, Berkeley for his bachelor’s degree in Molecular & Cell Biology (Neurobiology emphasis) and French. While at Cal, Axel was a research intern at the Gladstone Institutes at the University of California, San Francisco, and the Allen Institute for Brain Science in Seattle, working mainly in neurobiology and mouse models of Alzheimer’s disease. After graduation, Axel was drawn to genomics for its potential to transform the huge influxes of genetic data generated each day into deeper understanding of biology and potential therapies. Axel enrolled in the Genome Science and Technology program at UBC’s Michael Smith Laboratories in September 2019 and joined the Hirst Lab in January 2020. At the Hirst Lab, Axel’s research focuses on interpreting cell-type-specific epigenetic datasets and characterizing the interactions between various epigenetic marks and genetic variants in human breast tissue.


Axel Hauduca, Misha Bilenkyb, Annaick Carlesb, Jonathan Steifb, Michelle Moksaa, Qi Caoa, Connie Eavesc, Martin Hirsta

aUniversity of British Columbia, Vancouver, BC, Canada; bCanada’s Michael Smith Genome Sciences Centre, Vancouver, BC, Canada; cBC Cancer Research, Vancouver, BC, Canada

Interplay between the genome and the epigenome is fundamental to cell type functionality and the mechanisms of associated diseases. Most studies that have explored these interactions have leveraged population-scale genotype surveys to associate genetic polymorphisms with epigenetic states in whole blood or other heterogenous tissue types. Epigenetic states differ by cell type, raising the possibly of cell-type-specific genetic-to-epigenetic relationships that could drive specific functional states and disease predisposition. To address this, I mapped the epigenetic impact of genomic variants across a cohort of eight individuals in four distinct cell types of the human breast by searching for variant alleles strongly associated with histone modification peaks. I found that peak-associated variants were relatively enriched in active histone modification landscapes, drove allele-specific recruitment of active histone modifications, and disproportionately predicted transcription factor binding site creation/disruption events of transcription factors upregulated in the same cell type. Correlation with nearest-gene transcription allowed for the prioritization of functional candidates, and the regulatory impact of an ANXA1-linked variant, rs75071948, was observed uniquely in luminal cells, and validated in vitro using CRISPR-mediated HDR. Fascinatingly, previous work has noted contradictory effects of ANXA1 upregulation, with worsened outcomes for some breast cancers, such as triple negative, basal like, and invasive ductal carcinoma, but improved outcomes in ductal carcinoma in situ. Given the emergence of diseases in breast tissue, such as breast cancer, in distinct cell types, this study demonstrates the importance of assessing cell type when considering the impacts of genetic variants on regulation and disease.