Biology subjects

Gaynor, T. L.

Publications and source records attributed to Gaynor, T. L..

4 recordsLinked to original sources

bioRxiv2024

Single-cell transcriptional and epigenetic mapping reveals cellular and molecular mechanisms driving non-ischemic cardiac fibrosis

Cardiac fibrosis is a major cause of cardiac dysfunction. Recently, single-cell genomic approaches have revealed in unprecedented resolution the orchestrated cellular responses driving cardiac fibrosis. Yet, the fibrosis-causing phenotypes that emerge in the heart following non-ischemic cardiac stress, and the transcriptional circuits that govern cell identity and drive fibrosis, are not well understood. Applying a paired multiomic approach, we reveal key transcriptional circuits, in mouse and human hearts, which are associated with fibrosis development following non-ischemic cardiac insults, independent of disease model, species or biological sex. Strikingly, we find the key regulatory events driving fibrosis are reversible at the single-cell transcriptional and epigenomic level, further pointing to key factors regulating fibrosis development and resolution. The transcriptional regulators identified in this study represent promising targets to ameliorate the development of fibrosis in the context of chronic stressors such as aging and hypertension.

cell biology↗

bioRxiv2024

Single-nucleus RNA sequencing reveals cellular and molecular dynamics of white and brown adipose tissue in a mouse model of type-2 diabetes

Excessive adipose tissue expansion is often linked with type-2 diabetes. Despite recent efforts mapping adipose tissue changes in obesity using single-cell omics, an understanding of cellular and gene expression changes in a model of type 2 diabetes, and the transcriptional circuitry controlling it, is still lacking. Here, we use single-nucleus RNA sequencing to analyze the remodeling of gonadal white and interscapular brown adipose tissue from female and male mice with or without diabetes. Analysis of 51,877 nuclei revealed altered phenotypes in every cell population in type 2 diabetes. This included an immunoregulatory response, and changes in extracellular matrix, energy generation, and hormone responses. Key transcription factors were inferred as cell-specific and non-specific nodes controlling diabetes-linked phenotypes. Finally, female-to-male population heterogeneity and gene expression differences were observed. Here we provide a resource detailing how adipose tissue remodeling, and the molecular mechanisms governing it, may contribute to cardiometabolic disease.

cell biology↗

bioRxiv2021

CLARA: A web portal for interactive exploration of the cardiovascular cellular landscape in health and disease

Mammalian cardiovascular tissues are comprised of complex and diverse collections of cells. Recent advances in single-cell profiling technologies have accelerated our understanding of tissue cellularity and the molecular networks that orchestrate cardiovascular development, maintain homeostasis, and are disrupted in pathological states. Despite the rapid development and application of these technologies, many cardiac single-cell functional genomics datasets remain inaccessible for most cardiovascular biologists. Access to custom visual representations of the data, including querying changes in cellular phenotypes and interactions in diverse contexts, remains unavailable in publicly accessible data portals. Visualizing data is also challenging for scientists without expertise in processing single-cell genomic data. Here we present CLARA--CardiovascuLAR Atlas--a web portal facilitating exploration of the cardiovascular cellular landscape. Using mouse and human single-cell transcriptomic datasets, CLARA enables scientists unfamiliar with single-cell-omic data analysis approaches to examine gene expression patterns and the cell population dynamics of cardiac cells in a range of contexts. The web-application also enables investigation of intercellular interactions that form the cardiac cellular niche. CLARA is designed for ease-of-use and we anticipate that the portal will aid deeper exploration of cardiovascular cellular landscapes in the context of development, homeostasis and disease. CLARA is freely available at https://clara.baker.edu.au.

cell biology↗

bioRxiv2019

High-resolution transcriptomic profiling of the heart during chronic stress reveals cellular drivers of cardiac fibrosis and hypertrophy

BackgroundCardiac fibrosis is a key antecedent to many types of cardiac dysfunction including heart failure. Physiological factors leading to cardiac fibrosis have been recognized for decades. However, the specific cellular and molecular mediators that drive cardiac fibrosis, and the relative impact of disparate cell populations on cardiac fibrosis, remain unclear. MethodsWe developed a novel cardiac single-cell transcriptomics strategy to characterize the cardiac cellulome--the network of cells that forms the heart. This method was utilized to profile the cardiac cellular ecosystem in response to two weeks of continuous administration of Angiotensin II, a pro-fibrotic stimulus which drives pathological cardiac remodeling. ResultsThis analysis uncovered multiple cell populations contributing to pathological remodeling of the extracellular matrix of the heart. Two phenotypically distinct fibroblast populations emerged after induction of tissue stress to promote fibrosis in the absence of smooth muscle actin-expressing myofibroblasts, a key pro-fibrotic cell population. Further, the cellular responses to Angiotensin II and the relative abundance of fibrogenic cells were sexually dimorphic. ConclusionsThese results offer a valuable resource for exploring the cardiac cellular landscape in health and after chronic cardiovascular stress. These data provide insights into the cellular and molecular mechanisms that promote pathological remodeling of the mammalian heart, highlighting early transcriptional changes which precede chronic cardiac fibrosis.

cell biology↗