In human tissue there are sex-differences in gene regulation that are underpinning the observed sex-differences in sexually dimorphic traits and susceptibility to disease, but typical sex differences in gene expression remains poorly characterized. In humans, sex differences in gene expression occur prior to the development of gonads due to genetic differences between genetics males (46, XY) and genetic females (46, XX). The human placenta, which is the genotype of the fetus, forms within the first several days of gastrulation and plays a critical role in healthy fetal development by regulating nutrition and protecting the developing fetus from the mother?s immune system. Differences in gene content and gene regulation between placentas from males (46, XY) and females (46, XX) could contribute to observed sex differences in health and pregnancy complications. In fact, many severe pregnancy disorders including subchorionic hemorrhage, preeclampsia, preterm birth, and delivery by cesarean section, occur significantly more often in pregnancies with a male XY offspring than with a female XX offspring. Fetal growth and development vary between the sexes in part due to sex-differences in placental structure and function. Here we will analysis transcriptome and exome data from male XY and female XX human placenta samples from two non-adjacent placental locations to characterize genome-wide placental sex- differences in gene regulation and expression. Preliminary results of differential expression between 12 male and 12 female human placenta samples show that genes that are more highly expressed in the female samples are in involved in the stimulation of the ovaries to synthesize steroids for sustaining the pregnancy. Higher expressing genes in male placental samples are involved in T cell differentiation in immune response. The long- term objectives of the proposed research are to characterize gene-level, isoform-level, and allele specific expression differences and similarities between male XY and female XX placentas from healthy term placentas to generate a thorough overview of typical sex differences in placental immune regulation and expression. Additionally, we will leverage maternal decidua tissue to further understand how the maternal immune system is down regulated during pregnancy so as not to reject the developing fetus. In our proposal we will determine if maternal gene expression varies as a function of gestating either a male XY or female XX offspring, knowledge that is currently unknown. In the next two years of my Ph.D. program at Arizona State University (ASU), I will utilize ASU?s high- performance compute nodes to complete the proposed project on characterizing sex differences in the human placenta. I will get feedback on how best to interpret my findings by attending and presenting at weekly department journal clubs, lab meetings, and presenting at scientific conferences in the field of genomics research.
The placenta plays a critical role in healthy pregnancy by regulating nutrition and protecting the fetus from the mother?s immune system. Poor placentation may lead to severe pregnancy complications including preterm birth, intrauterine growth restriction, preeclampsia, and subchorionic hemorrhage, which show a sex difference in incidence. Here, we will characterize gene expression from full-term healthy placentas from male and female offspring and maternal decidua tissue to comprehensively understand the molecular mechanisms of expression in successful pregnancy.
