Ziqi Dong

All Publications

• Hypoxia promotes airway differentiation in the human lung epithelium CELL STEM CELL Dong, Z., Wit, N., Agarwal, A., Reid, A., Dubal, D., Beier, S., Mahbubani, K. T., Saeb-Parsy, K., van den Ameele, J., Nathan, J. A., Rawlins, E. L. 2025; 32 (11): 1705-1722

  Abstract

  Human lungs experience dynamic oxygen tension during development. Here, we show that hypoxia directly regulates human lung epithelial cell identity using tissue-derived organoids. Fetal multipotent lung epithelial progenitors remain undifferentiated in a self-renewing culture condition under normoxia but spontaneously differentiate toward multiple airway cell types and inhibit alveolar differentiation under hypoxia. Using chemical and genetic tools, we demonstrate that hypoxia-induced airway differentiation depends on hypoxia-inducible factor (HIF) activity, with HIF1α and HIF2α differentially regulating progenitor fate decisions. KLF4 and KLF5 are direct HIF targets that promote basal and secretory cell fates. Moreover, hypoxia is sufficient to convert alveolar type 2 cells derived from both human fetal and adult lungs to airway cells, including aberrant basal-like cells that exist in human fibrotic lungs. These findings reveal roles for hypoxia and HIF activity in the developing human lung epithelium and have implications for aberrant cell fate changes in pathological lungs.

  View details for DOI 10.1016/j.stem.2025.09.007

  View details for Web of Science ID 001614329900001

  View details for PubMedID 41075787

  View details for PubMedCentralID PMC7618356

• Deterministic nuclear reprogramming of mammalian nuclei to a totipotency-like state by Amphibian meiotic oocytes for stem cell therapy in humans BIOLOGY OPEN Wen, M., Triana, H., Butler, R., Hu, H., Dai, Y., Lawrence, N., Hong, J., Garrett, N., Jones-Green, R., Rawlins, E. L., Dong, Z., Koziol, M. J., Gurdon, J. B. 2024; 13 (3)

  Abstract

  The ultimate aim of nuclear reprogramming is to provide stem cells or differentiated cells from unrelated cell types as a cell source for regenerative medicine. A popular route towards this is transcription factor induction, and an alternative way is an original procedure of transplanting a single somatic cell nucleus to an unfertilized egg. A third route is to transplant hundreds of cell nuclei into the germinal vesicle (GV) of a non-dividing Amphibian meiotic oocyte, which leads to the activation of silent genes in 24 h and robustly induces a totipotency-like state in almost all transplanted cells. We apply this third route for potential therapeutic use and describe a procedure by which the differentiated states of cells can be reversed so that totipotency and pluripotency gene expression are regained. Differentiated cells are exposed to GV extracts and are reprogrammed to form embryoid bodies, which shows the maintenance of stemness and could be induced to follow new directions of differentiation. We conclude that much of the reprogramming effect of eggs is already present in meiotic oocytes and does not require cell division or selection of dividing cells. Reprogrammed cells by oocytes could serve as replacements for defective adult cells in humans.

  View details for DOI 10.1242/bio.060011

  View details for Web of Science ID 001198114700008

  View details for PubMedID 37982514

  View details for PubMedCentralID PMC10924218

• One-carbon metabolism is required for epigenetic stability in the mouse placenta FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY Senner, C. E., Dong, Z., Prater, M., Branco, M. R., Watson, E. D. 2023; 11: 1209928

  Abstract

  One-carbon metabolism, including the folate cycle, has a crucial role in fetal development though its molecular function is complex and unclear. The hypomorphic Mtrr gt allele is known to disrupt one-carbon metabolism, and thus methyl group availability, leading to several developmental phenotypes (e.g., neural tube closure defects, fetal growth anomalies). Remarkably, previous studies showed that some of the phenotypes were transgenerationally inherited. Here, we explored the genome-wide epigenetic impact of one-carbon metabolism in placentas associated with fetal growth phenotypes and determined whether specific DNA methylation changes were inherited. Firstly, methylome analysis of Mtrr gt/gt homozygous placentas revealed genome-wide epigenetic instability. Several differentially methylated regions (DMRs) were identified including at the Cxcl1 gene promoter and at the En2 gene locus, which may have phenotypic implications. Importantly, we discovered hypomethylation and ectopic expression of a subset of ERV elements throughout the genome of Mtrr gt/gt placentas with broad implications for genomic stability. Next, we determined that known spermatozoan DMRs in Mtrr gt/gt males were reprogrammed in the placenta with little evidence of direct or transgenerational germline DMR inheritance. However, some spermatozoan DMRs were associated with placental gene misexpression despite normalisation of DNA methylation, suggesting the inheritance of an alternative epigenetic mechanism. Integration of published wildtype histone ChIP-seq datasets with Mtrr gt/gt spermatozoan methylome and placental transcriptome datasets point towards H3K4me3 deposition at key loci. These data suggest that histone modifications might play a role in epigenetic inheritance in this context. Overall, this study sheds light on the mechanistic complexities of one-carbon metabolism in development and epigenetic inheritance.

  View details for DOI 10.3389/fcell.2023.1209928

  View details for Web of Science ID 001026686400001

  View details for PubMedID 37440923

  View details for PubMedCentralID PMC10333575

• A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates CELL He, P., Lim, K., Sun, D., Pett, J., Jeng, Q., Polanski, K., Dong, Z., Bolt, L., Richardson, L., Mamanova, L., Dabrowska, M., Wilbrey-Clark, A., Madissoon, E., Tuong, Z., Dann, E., Suo, C., Goh, I., Yoshida, M., Nikolic, M. Z., Janes, S. M., He, X., Barker, R. A., Teichmann, S. A., Marioni, J. C., Meyer, K. B., Rawlins, E. L. 2022; 185 (25): 4841-+

  Abstract

  We present a multiomic cell atlas of human lung development that combines single-cell RNA and ATAC sequencing, high-throughput spatial transcriptomics, and single-cell imaging. Coupling single-cell methods with spatial analysis has allowed a comprehensive cellular survey of the epithelial, mesenchymal, endothelial, and erythrocyte/leukocyte compartments from 5-22 post-conception weeks. We identify previously uncharacterized cell states in all compartments. These include developmental-specific secretory progenitors and a subtype of neuroendocrine cell related to human small cell lung cancer. Our datasets are available through our web interface (https://lungcellatlas.org). To illustrate its general utility, we use our cell atlas to generate predictions about cell-cell signaling and transcription factor hierarchies which we rigorously test using organoid models.

  View details for DOI 10.1016/j.cell.2022.11.005

  View details for Web of Science ID 000901773800002

  View details for PubMedID 36493756

  View details for PubMedCentralID PMC7618435

• Chaperoning RPA during DNA metabolism CURRENT GENETICS Li, S., Dong, Z., Yang, S., Feng, J., Li, Q. 2019; 65 (4): 857-864

  Abstract

  Single-stranded DNA (ssDNA) is widely generated during DNA metabolisms including DNA replication, repair and recombination and is susceptible to digestion by nucleases and secondary structure formation. It is vital for DNA metabolism and genome stability that ssDNA is protected and stabilized, which are performed by the major ssDNA-binding protein, and replication protein A (RPA) in these processes. In addition, RPA-coated ssDNA also serves as a protein-protein-binding platform for coordinating multiple events during DNA metabolisms. However, little is known about whether and how the formation of RPA-ssDNA platform is regulated. Here we highlight our recent study of a novel RPA-binding protein, Regulator of Ty1 transposition 105 (Rtt105) in Saccharomyces cerevisiae, which regulates the RPA-ssDNA platform assembly at replication forks. We propose that Rtt105 functions as an "RPA chaperone" during DNA replication, likely also promoting the assembly of RPA-ssDNA platform in other processes in which RPA plays a critical role.

  View details for DOI 10.1007/s00294-019-00945-3

  View details for Web of Science ID 000475695500006

  View details for PubMedID 30796471