Germ cells are often considered immortal. They are the sole messengers to relay genetic and epigenetic information across generations to perpetuate life. The germline cycle is long with specification starting from early gastrulation to gametogenesis continuing after birth. Errors occurring at any stage during this process can lead to devastating and long-lasting effects. With recent technological advances in single-cell sequencing, our knowledge of germline development in mammals has expanded considerably in recent times but some questions remain. Among them, we aim to answer (1) what regulates progenitor competence and then define cell quality to opt into germline specification? (2) How is migration correlated with epigenetic remodeling? (3) How certain genetic mutations affect gametogenesis?

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Interestingly, two waves of epigenetic remodeling occur after fertilization to ensure the totipotency of the blastocyst for somatic lineage specification and to ascertain the “clean slate” of germ cells for erasing any potentially harmful epigenetic modifications acquired by parents. The evolutionary advantage of these processes is to enable the organism to adapt to changing environmental conditions and minimize the risk of epigenetic inheritance of harmful traits. However, the degree of completeness and faithfulness of these processes remains to be investigated. More and more studies have shown that parental health condition predisposes their offspring to develop diseases such as obesity, diabetes, cardiovascular disease, and behavioral disorders, which contribute to the increased prevalence of chronic diseases. This process is referred to as developmental programming and epigenetic inheritance of diseases. Despite of increasing amount of epidemiological evidence, mechanistic understanding is still sparse. Here, we aim to answer (1) how parental health condition affects the germline that further transmits phenotypic traits? (2) how the placenta responds to an adverse uterine environment that in turn systematically modifies the cellular and physiological function of the offspring? (3) can we systematically model maternal disease signature with offspring key organ signature?

 

We are among those pioneers in 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.