Yingshu Li | Tu Lab

Tatdn2 is required for DNA repair to safeguard genome stability in primordial germ cells

Fri, 19 Dec 2025 00:00:00 +0000

Maintaining genome integrity in germ cells is crucial for fertility and species survival. However, the DNA repair mechanisms that sustain genome integrity in primordial germ cells (PGCs), which cope with high levels of replication stress, remain largely unknown. While the TatD family of proteins, evolutionarily conserved nucleases, has been found to play roles in various DNA-related processes, their in vivo functions in vertebrates have yet to be fully elucidated. TATDN2 has recently been implicated in resolving R-loops and participating in the replication stress response in BRCA1-deficient cancer cells. Here we found that tatdn2 exhibits conserved expression in mitotic and early meiotic germ cells across teleosts and mammals. Using medaka fish as a model, we then showed that loss of tatdn2 leads to all-phenotypically male adults and infertility due to PGC depletion during mitotic proliferation. We further demonstrated that knockout of tatdn2 increases R-loop accumulation and DNA damage, subsequently triggering apoptosis in PGCs. These findings indicate that tatdn2 plays a critical role in DNA damage repair associated with R-loop resolution in mitotic PGCs. Our study provides novel insights into the physiological function of TATDN2 and the mechanisms of genome maintenance in PGCs.

From Understudied to Understood: Multi-Omics Analysis with MiniENCODE Exemplified by Zebrafish

Mon, 01 Jan 2024 00:00:00 +0000

Abstract: The ENCODE project provides a comprehensive map of genomic activity in humans and mice. However, its extensive toolbox can be too costly and technically challenging for smaller research communities. This presents a hurdle for understudied model organisms where resource constraints and complex omics data integration further compound the challenge. To bridge this gap, our study introduces a miniENCODE project, using the zebrafish as an exemplar. We collected, generated and integrated datasets from three experimental assays across developmental stages and adult tissues. This analysis is facilitated by our newly developed miniODP database, a computational tool designed for the integration and visualization of multi-omics data. Utilizing these methods, we have cataloged over 52,000 candidate enhancers, identified various stage-specific, tissue-specific, and constantly active enhancers, and experimentally validated a subset of heart-specific enhancers. We have delineated key transcription factors and their corresponding regulatory networks across developmental stages and adult tissues. This study not only delivers valuable regulatory insights for the zebrafish research community but also illustrates how an integrative approach can aid in understanding complex regulatory mechanisms even with limited resources. This strategy could empower scientific communities working with various understudied model organisms to expedite their genomic research without overstretching their resources.Competing Interest StatementThe authors have declared no competing interest.

Dynamic Transcriptional and Chromatin Accessibility Landscape of Medaka Embryogenesis

Fri, 26 Jun 2020 00:00:00 +0000

Abstract: Medaka (Oryzias latipes) has become an important vertebrate model widely used in genetics, developmental biology, environmental sciences, and many other fields. A high-quality genome sequence and a variety of genetic tools are available for this model organism. However, existing genome annotation is still rudimentary, as it was mainly based on computational prediction and short-read RNA-seq data. Here we report a dynamic transcriptome landscape of medaka embryogenesis profiled by long-read RNA-seq, short-read RNA-seq, and ATAC-seq. Integrating these datasets, we constructed a much-improved gene model set including about 17,000 novel isoforms, identified 1600 transcription factors, 1100 long non-coding RNAs, and 150,000 potential cis-regulatory elements as well. Time-series datasets provided another dimension of information. With the expression dynamics of genes and accessibility dynamics of cis-regulatory elements, we investigated isoform switching, regulatory logic between accessible elements and genes during embryogenesis. We built a user-friend medaka omics data portal to present these datasets. This resource provides the first comprehensive omics datasets of medaka embryogenesis. Ultimately, we term these three assays as the minimum ENCODE toolbox and propose the use of it as the initial and essential profiling genomic assays for model organisms that have limited data available. This work will be of great value for the research community using medaka as the model organism and many others as well.

Decode-Seq: A Practical Approach to Improve Differential Gene Expression Analysis

Mon, 23 Mar 2020 00:00:00 +0000

Abstract: Many differential gene expression analyses are conducted with an inadequate number of biological replicates. We describe an easy and effective RNA-seq approach using molecular barcoding to enable profiling of a large number of replicates simultaneously. This approach significantly improves the performance of differential gene expression analysis. Using this approach in medaka (Oryzias latipes), we discover novel genes with sexually dimorphic expression and genes necessary for germ cell development. Our results also demonstrate why the common practice of using only three replicates in differential gene expression analysis should be abandoned.