Date of Degree


Document Type


Degree Name





Zahra F. Zakeri

Subject Categories

Cell Biology | Developmental Biology | Molecular Biology


Alcohol, Estrogen, Gender, Hormones, Methylation, Sex


Male and female differences in frequency of occurrence in disease have perplexed scientists for some time. This in part derives from limitations in the systems in which one can evaluate sex differences. At the organismal level, differences can be hidden by a myriad of extensive and complex factors. Additional limitations exist since most biomedical studies are performed almost exclusively on male subjects, as the female hormonal milieu is intrinsically more variable and too troublesome for routine inclusion in research protocols. Research documenting sex differences continues to grow, and while most researchers suggests that sex hormones are at the core of these differences, more evidence is suggesting other innate biological factors are at play.

To address these limitations, we asked whether differences could be induced and assessed in a controlled cellular system. We then asked whether any aspect of sex dimorphism could be attributed to chromosomal rather than hormonal differences; and finally established a role for differential DNA methylation in sex differences.

We found that male and female cells responded differently to cell death inducers as measured by cell viability. We then evaluated gene expression between the sexes, and found that many genes were differentially expressed in vivo. These differences persisted in our cultures, affording us the ability to further characterize these sex differences.

Furthermore, we found that cell death induction led to dimorphic gene expression; at instances having opposite effects on cells, where one sex is repressed, and the other is induced.

We then evaluated DNA methylation to characterize the differential gene regulation. Blocking DNA methylation globally, using 5-Aza-2-deoxycytidine, led to a loss of gene expression differences between the sexes and found that differences in methylation patterns correlated directly with differences in gene expression.

Here we provided a model system, whereby we can test for individual differences resulting in sex dimorphisms at the cellular level. It is critical to continue to expand our knowledge in this area, as this work can be extrapolated and applied to other instances where differences are being measured between the sexes; providing more tools to better characterize those conditions.