Biology subjects

Tran, B. T.

Publications and source records attributed to Tran, B. T..

3 recordsLinked to original sources

bioRxiv2024

Let-7 restrains an oncogenic epigenetic circuit in alveolar type 2 cells to prevent ectopic formation of fibrogenic AT2 intermediates and pulmonary fibrosis

Analysis of lung alveolar type 2 (AT2) progenitor stem cells has highlighted fundamental mechanisms that direct their differentiation into alveolar type 1 cells (AT1s) in lung repair and disease. However, microRNA (miRNA) mediated post-transcriptional mechanisms which govern this nexus remain understudied. We show here that the let-7 miRNA family serves a homeostatic role in governance of AT2 quiescence, specifically by preventing the uncontrolled accumulation of AT2 transitional cells and by promoting AT1 differentiation. Using mice and organoid models, we demonstrate genetic ablation of let-7a1/let-7f1/let-7d cluster (let-7afd) in AT2 cells prevents AT1 differentiation and results in accumulation of AT2 transitional cells in progressive pulmonary fibrosis. Integration of AGO2-eCLIP with RNA-sequencing from AT2 cells uncovered the induction of direct targets of let-7 in an oncogene feed-forward regulatory network including BACH1/EZH2/MYC which drives an aberrant fibrotic cascade. Additional analyses using CUT&RUN-sequencing revealed an epigenetic role of let-7 in induction of chromatin histone acetylation and methylation and maladaptive AT2 cell reprogramming. This study identifies let-7 as a key gatekeeper of post-transcriptional and epigenetic chromatin signals to prevent AT2-driven pulmonary fibrosis.

cell biology↗

bioRxiv2023

Multiomics of human aortic endothelial cells reveals cell subtypes with heterogeneous responses to canonical endothelial-to-mesenchymal perturbations

ObjectiveEndothelial cells (ECs), macrophages, and vascular smooth muscle cells (VSMCs) are major cell types in atherosclerosis progression, and heterogeneity in EC sub-phenotypes are becoming increasingly appreciated. Still, studies quantifying EC heterogeneity across whole transcriptomes and epigenomes in both in vitro and in vivo models are lacking. Approach and ResultsTo create an in vitro dataset to study human EC heterogeneity, multiomic profiling concurrently measuring transcriptomes and accessible chromatin in the same single cells was performed on six distinct primary cultures of human aortic ECs (HAECs). To model pro-inflammatory and activating environments characteristic of the atherosclerotic microenvironment in vitro, HAECs from at least three donors were exposed to three distinct perturbations with their respective controls: transforming growth factor beta-2 (TGFB2), interleukin-1 beta (IL1B), and siRNA-mediated knock-down of the endothelial transcription factor ERG (siERG). To form a comprehensive in vivo/ex vivo dataset of human atherosclerotic cell types, meta-analysis of single cell transcriptomes across 17 human arterial specimens was performed. Two computational approaches quantitatively evaluated the similarity in molecular profiles between heterogeneous in vitro and in vivo cell profiles. HAEC cultures were reproducibly populated by 4 major clusters with distinct pathway enrichment profiles: EC1-angiogenic, EC2-proliferative, EC3-activated/mesenchymal-like, and EC4-mesenchymal. Exposure to siERG, IL1B or TGFB2 elicited mostly distinct transcriptional and accessible chromatin responses. EC1 and EC2, the most canonically healthy EC populations, were affected predominantly by siERG; the activated cluster EC3 was most responsive to IL1B; and the mesenchymal population EC4 was most affected by TGFB2. Quantitative comparisons between in vitro and in vivo transcriptomes confirmed EC1 and EC2 as most canonically EC-like, and EC4 as most mesenchymal with minimal effects elicited by siERG and IL1B. Lastly, accessible chromatin regions unique to EC2 and EC4 were most enriched for coronary artery disease (CAD)-associated SNPs from GWAS, suggesting these cell phenotypes harbor CAD-modulating mechanisms. ConclusionPrimary EC cultures contain markedly heterogeneous cell subtypes defined by their molecular profiles. Surprisingly, the perturbations used here, which have been reported by others to be involved in the pathogenesis of atherosclerosis as well as induce endothelial-to-mesenchymal transition (EndMT), only modestly shifted cells between subpopulations, suggesting relatively stable molecular phenotypes in culture. Identifying consistently heterogeneous EC subpopulations between in vitro and in vivo models should pave the way for improving in vitro systems while enabling the mechanisms governing heterogeneous cell state decisions.

genomics↗

bioRxiv2022

Genetic diversity assessment of Pacific oyster Magallana gigas (Crassostrea gigas) populations from the two southern coastal farms in South Korea

South Korea is among the major producers of the Pacific oyster, Magallana gigas (Crassostrea gigas), which is one of the most valued aquaculture species. Since the early 1990s, climatic and anthropogenic factors have incurred the reduction of their wild seeds, whereby the dependence on hatchery-produced seeds has constantly increased in South Korea, thus raising concerns about losing genetic diversity and accelerating genetic deterioration. To better understand their genetic make-up, we assessed the genetic diversity of M. gigas populations from two farms (Tongyeong and Gadeokdo) in the southern coast, where about 80% of the cultivated oysters in Korea are produced. Tongyeong showed slightly higher diversity than Gadeokdo, but both populations had a similar genetic structure characterized by low nucleotide diversity. Comparative haplotype analyses provided data supporting unique genetic features of the populations that include (1) weak genotype-locality relationship, (2) low levels of gene flow between populations, and (3) seasonal fluctuation of genetic variation within a population. Furthermore, the highly alike haplotype network patterns were observed between the wild and farm populations as well as among the populations in neighboring countries, which suggests that the genetic structure is conserved between wild and hatchery populations, and geographic proximity has minimal influence on the genetic composition. These results warrant further study in biological and ecological contexts and will be invaluable in formulating genetic monitoring and sustainable long-term management of M. gigas.

genetics↗