Germ cell biology · Developmental programming · Epigenetic inheritance of disease
ABOUT OUR
RESEARCH.
Building on foundational contributions in germ cell biology,
our early work defined key regulatory principles governing human and mouse germline specification, including formative pluripotency, X-chromosome dosage control, and mitochondrial dynamics during developmental transitions. This expertise provides a mechanistic framework for understanding how parental environments can influence the next generation at the earliest biological level.
We have since expanded this framework to maternal-fetal interactions in developmental programming.
Rather than viewing the placenta as a passive conduit, our research conceptualizes it as an adaptive signaling hub that senses maternal endocrine and metabolic states and actively transmits information to the developing fetus. We focus on how maternal diseases, including diabetes and polycystic ovary syndrome, reprogram the uterine environment that alter cellular, immune, and metabolic pathways in key metabolic organs with lasting consequences for offspring health.
Our long-term goal is to identify early molecular responders to maternal health conditions
and move beyond descriptive associations toward causal mechanisms, enabling early detection and prevention of cardiometabolic diseases.
I.
Investigate the role of germline transmission in epigenetic inheritance of diseases
Women are born with a pool of primary follicles, some of which are periodically matured for fertilization. Throughout a woman's reproductive life, the number and quality of the remaining follicles gradually decline, leading to a decrease in fertility and an increased risk of reproductive disorders. Besides genetics, environmental factors can affect the health and function of the oocytes through dynamic interaction with niche cells. We are particularly interested in how maternal endocrine diseases such as polycystic ovarian syndrome (PCOS) and type I diabetes impact the transcriptome and metabolism of oocytes, which in turn affects their offspring's health across generations independent of uterine environmental effects. We are using diseased mouse models, IVF and surrogacy, and single-cell sequencing together with phenotyping and molecular assays.
II.
Investigate the molecular basis of maternal-fetal communication in maternal endocrine diseases and their effects on offspring's future health
We have previously shown that reproductive and metabolic traits of maternal PCOS can be transmitted across generations (Risal, Pei et.al. Nature Medicine 2019). To further delineate the role of adverse uterine environment versus germline transmission, we are carrying on several projects to study the role of the placenta in developmental programming and offspring’s future health. As increasing evidence has shown that the placenta is not functioned as a passive barrier, instead actively responds and adapts to uterine environment to impact fetal development. It is important to elucidate molecular adaptation of placentas in maternal endocrine diseases in function to maternal clinical features including hormone profiles. We also aim to mediate the placental function and prevent the developmental programming. To address these questions, mouse disease models, single-cell sequencing of human placentas as well placental organoids based chemical screening are applied to systematically examine molecular and phenotypic traits of mother, placentas and offspring and build molecular link underlying the developmental programming effects.
III.
Develop a culture platform to differentiate germ cells towards maturation with epigenetic remodeling to model diseases and gain mechanistic understanding
The use of pluripotent stem cells for in vitro differentiation provides a valuable approach to study human germ cell specification and to uncover genetic and epigenetic dysregulations associated with infertility. Our previous and recent work has demonstrated the establishment of formative pluripotency conditions for direct specification of primordial germ cell-like cells (PGCLCs) (Cheng et.al Cell Reports 2019, Luo et.al Cell Reports 2023).
Building on this work, we plan to further develop in vitro differentiation platform using organoid co-culture to investigate the impact of genetic mutations on fertility. Specifically, our research has shown a focus on understanding the role of X-chromosome activity and mitochondrial dynamics in germ cell development.
IV.
Characterize the spatiotemporal regulation of germ cell migration and reveal the mechanisms of quality selection for gametogenesis
Germ cell migration is accompanied by extensive DNA demethylation and histone protein modification. We still know little about how these two sophisticated processes are coordinated. Furthermore, majority of migrating germ cells undergo apoptosis without further commitment to gametogenesis. We aim to use genetic mouse models, lineage tracing, single-cell sequencing among others to reveal gene function and mitochondrial dynamics during migration, epigenetic resetting, and meiosis entry. Especially, we are focusing on human genetic mutations implicated in infertility/subfertility.
We are among the pioneers applying and developing single-cell RNA sequencing (Smart-seq, Smart-seq2, LCM-seq, etc).
More tools to answer all these interesting questions are mouse disease models, human iPSC culture and differentiation, organoid culture, human sample cohorts and registry data...
together with other key cellular and molecular assays.