When Yulong Liu was in elementary school, he made what he now refers to as a “naive childhood promise” to his mother. Fueled by love, he vowed to create a miracle drug capable of bestowing eternal life.
“Though I realized the improbability of my promise, I developed a fascination with biology and science in general,” he said. “During my undergraduate study at Arizona State University, I gained a keen interest in stem cell biology and regenerative medicine.”
That interest grew during his graduate studies at the UC Davis College of Biological Sciences.
As a Ph.D. student in the Biochemistry, Molecular, Cellular and Developmental Biology Graduate Group, Liu now investigates the cellular mechanisms underlying female reproductive development in the lab of Associate Professor Bruce Draper, Department of Molecular and Cellular Biology. Using zebrafish (Danio rerio) as a model organism, he and his colleagues performed single-cell RNA sequencing analyses to map the genetic expression of individual cells in the zebrafish ovary, with hopes of mapping the genetic cues responsible for regulating reproductive development. The research could help scientists identify genetic factors contributing to germ cell development and reproductive diseases, like infertility.
For his research, Liu was recently awarded the UC Davis Dissertation Year Fellowship.
“I’m super grateful that there’s this award out there to help us support the dissertation,” said Liu, who hopes to complete his doctoral program in June 2021. “The award guarantees us funding for the last year so we can just focus on finishing our dissertation research.”
A niche for life
For many organisms, life relies on germline stem cells. Produced by testes and ovaries, these cells are directly responsible for the production of eggs and sperm. Yet, there’s much scientists don’t understand about the microenvironments of reproductive organs and how those microenvironments influence reproductive development.
In the mammalian world, only males are known to produce sex cells (sperm) from germline stem cells throughout their entire lifecycle. Females, current theories suggest, are born with a finite number of sex cells (eggs). And while genes responsible for regulating germline stem cells in mammalian males have been identified, the same can’t be said for any female vertebrates.
This is where zebrafish come in handy. Females can lay up to 200 eggs per week, and their proclivity for reproduction, and similarities to humans as fellow vertebrates, makes them a popular model organism for studying reproductive diseases and infertility.
"My research focuses on the germline stem cells, so stem cell populations that make germ cells, the eggs and sperm,” said Liu. “The main question here is, 'How are germline stem cells regulated?’”
The hypothesis-generating machine
To get a high-resolution view of the development of female germline stem cells in zebrafish, Liu and his colleagues, in collaboration with Assistant Professor of Molecular and Cellular Biology Celina Juliano’s lab, performed single-cell RNA sequencing analyses, a technique that allows the tracking of a single cell’s full suite of gene expressions, known as the transcriptome.
The researchers performed analyses on more than 10,000 female germ cells and 14,000 somatic gonad cells, tracking the genetic expressions of each cell as it developed. Somatic gonad cells are non-reproductive cells in the ovary’s microenvironment.
Outfitted with this dizzying dataset for tens of thousands of cells, Liu and his colleagues identified different groups of germs cells and somatic gonad cells, clustering them together based on similarities in their gene expressions. They were able to trace the genetic trajectory of female germ cells through development, from germline stem cell differentiation all the way to egg production, known as oogenesis. They also characterized the genetic expression of nearby somatic gonad cells and identified niche cell types.
“Our transcriptome dataset of the zebrafish ovary expression landscape offers a valuable resource for female germ cell differentiation, meiosis, reproduction and ovarian cancer research,” said Liu.
To accomplish this task, Liu had to teach himself computational biology techniques like R programming for data analysis. For him, the relationship between wet lab work and computational biology is paramount to advancing the life sciences. Insights gleaned from computational analyses can lead to new avenues of inquiry.
"I always call single-cell RNA sequencing the hypothesis generating machine,” he said.