Single-cell transcriptomic analyses of early embryonic development and developmental programming by androgen excess
Infertility is a compelling problem an increased prevalence among couples. Although multiple causes have been hypothesized to increase the risk of infertility, changes in lifestyles and environment are the possible links to the causes. While germ cells represent the eternal link between generations, epigenetic modification in germ cells provides a conceivable link between the environmental influences and alterations in gene expression across generations. During embryonic development, there are several important processes that can affect fertility, including germ cell specification, germ cell migration along hindgut, germ cell localization at gonads, sex differentiation and further stages of gametogenesis.
We are particularly interested in polycystic ovarian syndrome (PCOS) as it is the main cause of infertility worldwide. PCOS is highly heritable, with estimated 70% familial heritability. However, in total, 19 loci significantly linked to PCOS from genome-wide association studies (GWAS) only account for ~10% of its heritability. Recent studies suggest that epigenetic regulation of embryonic development and germline modification resulting from hyperandrogenism in the uterine environment contribute to the onset of PCOS in offspring and across generations.
This thesis includes three studies to understand the possible causes related to infertility during early embryonic development and germline. The aim of Study I is to investigate cellular heterogeneity of epiblast during early embryonic development by single-cell transcriptomic analysis. The aim of Study II is to investigate whether prenatal androgen exposure leads to transgenerational transmission of PCOS. The aim of Study III is to study molecular effects of fetal and adult programming by androgen in different PCOS-like mouse models as well as a maternal obesity mouse model by transcriptional profiling of key organs.
List of scientific papers
I. Single-Cell RNA-Seq Reveals Cellular Heterogeneity of Pluripotency Transition and X Chromosome Dynamics during Early Mouse Development. Cheng S*, Pei Y*, He L, Peng G, Reinius B, Tam PPL, Jing N, Deng Q. Cell Rep. 2019 Mar 5; 26(10):2593-2607. *Equal contribution.
https://doi.org/10.1016/j.celrep.2019.02.031
II. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Risal S*, Pei Y*, Lu H*, Manti M, Fomes R, Pui HP, Zhao Z, Massart J, Ohlsson C, Lindgren E, Crisosto N, Maliqqueo M, Echiburu B, Ladron de Guevara A, Sir-Petemann T, Larsson H, Rosenqvist MA, Cesta CE, Benrick A, Deng Q, Stener-Victorin E. Nature Medicine. 25, 1894-1904(2019). *Equal contribution.
https://doi.org/10.1038/s41591-019-0666-1
III. Transcriptomic mapping of key reproductive and metabolic tissues and oocytes in mouse models of polycystic ovary syndrome. Pei Y*, Risal S*, Jiang H, Lu H, Lindgren E, Stener-Victorin E*, Deng D*. *Equal contribution. [Manuscript]
History
Defence date
2022-09-09Department
- Department of Physiology and Pharmacology
Publisher/Institution
Karolinska InstitutetMain supervisor
Deng, QiaolinCo-supervisors
Stener-Victorin, Elisabet; Ericson, Johan; Ramsköld, DanielPublication year
2022Thesis type
- Doctoral thesis
ISBN
978-91-8016-749-9Number of supporting papers
3Language
- eng