Biology subjects

Flygare, J.

Publications and source records attributed to Flygare, J..

3 recordsLinked to original sources

bioRxiv2025

Transcriptional Roadmap of the Human Airway Epithelium Identifying HLF as a Novel Regulator of Basal Stem Cell Function

RationaleThe human airway epithelium depends on a coordinated hierarchy of stem-and differentiated cells to maintain tissue integrity and respond to injury. Defining the transcriptional and translational programs that govern these processes is critical for understanding airway disease and advancing regenerative therapies. ObjectivesTo map the transcriptional landscape of the human airway epithelium and identify regulatory factors controlling basal stem cell function and epithelial differentiation. MethodsWe performed single-cell RNA sequencing on bronchial biopsies from nine healthy never-smokers, categorized into young (<40 years) and aged (>60 years) cohorts. Unbiased cell type annotation and pseudotime trajectory analysis were used to define cell states and transcription factor dynamics. Measurements and Main ResultsAll major airway epithelial cell types were identified, with conserved composition and transcriptional programs across age groups. Basal stem cells (BSCs) exhibited elevated ribosomal gene expression, indicating increased translational readiness. Pseudotime analysis revealed transitions from basal to differentiated states, with MYC, JUN, and FOS upregulated in proliferative suprabasal cells. HLF emerged as a BSC-enriched transcription factor downregulated upon differentiation. Functional assays showed that HLF overexpression suppresses proliferation in airway BSC and in lung squamous carcinoma cells, while Hlf-deficient mice display basal cell hyperplasia and deficient differentiation. In lung cancer datasets, low HLF expression correlated with worse patient survival. ConclusionsThis study defines conserved gene programs in the human airway epithelium and identifies HLF as a novel regulator of BSC proliferation and potential tumor suppressor. These findings may inform the development of regenerative therapies and contribute to improved understanding and treatment of lung disease.

molecular biology↗

bioRxiv2023

VelosGT: An App for Variant Analysis and Rare Disease Discovery

VelosGT is a MacOS application to analyze human genomes for genetic mutation and rare disease. It consumes raw read files (fasta/fastq) and returns annotated, functionally prioritized variants in a single step, while significantly out-performing standard pipelines. VelosGT ingests short-read data in all common formats (fastq, fasta, fastq.gz, and fasta.gz) as well as paired data. It can perform analyses on single genomes (proband) or trios. The underlying algorithms have been optimized to the extent that it can run directly on a personal computer, with no additional hardware required. This increases convenience and speed because no large uploads or downloads are required. All discovered variants are immediately displayed and searchable within the app. On an average* Mac laptop, VelosGT will return the results of a high-coverage 30GB read file in under an hour, and a 5GB read file in ten minutes or less. Trios can be computed using the completed child-parent analyses in a few minutes.

bioinformatics↗

bioRxiv2021

Nuclear stabilisation of p53 requires a functional nucleolar surveillance pathway

The nucleolar surveillance pathway (NSP) monitors nucleolar fidelity and responds to nucleolar stresses (i.e., inactivation of ribosome biogenesis) by mediating the inhibitory binding of ribosomal proteins (RPs) to mouse double minute 2 homolog (MDM2), a nuclear-localised E3 ubiquitin ligase, which results in p53 accumulation. Inappropriate activation of the NSP has been implicated in the pathogenesis of collection of human diseases termed "ribosomopathies", while drugs that selectively activate the NSP are now in trials for cancer. Despite the clinical significance, the precise molecular mechanism(s) regulating the NSP remain poorly understood. Using genome-wide loss of function screens, we demonstrate the ribosome biogenesis (RiBi) axis as the most potent class of genes whose disruption stabilises p53. Furthermore, we identified a novel suite of genes critical for the NSP, including a novel mammalian protein implicated in 5S ribonucleoprotein particle (5S-RNP) biogenesis, HEATR3. By selectively disabling the NSP, we unexpectedly demonstrate that a functional NSP is required for the ability of all nuclear acting stresses tested, including DNA damage, to robustly induce p53 accumulation. Together, our data demonstrates that the NSP has evolved as the dominant central integrator of stresses that regulate nuclear p53 abundance, thus ensuring RiBi is hardwired to cellular proliferative capacity.

cell biology↗