Biology subjects

Powell, J. A.

Publications and source records attributed to Powell, J. A..

3 recordsLinked to original sources

bioRxiv2025

NETSseq Reveals Inflammatory and Aging Mechanisms in Distinct Cell Types Driving Cerebellar Decline in Ataxia Telangiectasia

The cellular and molecular changes driving the neurological abnormalities associated with ataxia - telangiectasia (A-T) are not well understood. Here, we applied our proprietary Nuclear Enriched Transcript Sort sequencing (NETSseq) platform to investigate changes in cell type composition and gene expression in human cerebellar post-mortem tissue from A-T and control donors. Compared to single-nuclei technologies, NETSseq provided a more robust detection of genes with low abundance, a higher cell type specific expression pattern, and significantly lower levels of cross-contamination. We found dysregulation in neurotransmitter signaling in granule neurons, potentially underlying the impaired motor coordination in A-T. Astrocytes and microglia have evidence of accelerated aging, with astrocytes being characterized by neurotoxic signatures, while microglia showed activation of DNA damage response pathways. These findings highlight the importance of NETSseq as a resource for investigating mechanisms and biological processes associated with disease, providing high-sensitivity, cell-specific insights to advance targeted therapies for neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukaemia.

The ubiquitous metabolite heme has diverse enzymatic and signalling functions in most mammalian cells. Cells can salvage heme from the extracellular environment or synthesise heme de novo from succinyl-CoA and glycine through a series of 8 enzymatic reactions catalysed by heme biosynthesis enzymes (HBEs) localised in the mitochondria and the cytosol1,2. Through integrated analyses of mouse models, human cell lines and primary patient samples, we identify de novo heme biosynthesis as a selective dependency in acute myeloid leukaemia (AML). The dependency is underpinned by a propensity of AML cells, and especially leukaemic stem cells (LSCs) to downregulate HBEs. The resultant low heme state upregulates self-renewal genes via the heme sensing transcription factor BACH1, but also places leukaemia cells on the threshold of heme starvation. Genetic or pharmacological inhibition of HBEs induces cuproptosis, a form of programmed cell death caused by copper accumulation and oligomerisation of lipoylated proteins3. Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies. Altogether, our work uncovers a heme rheostat that controls gene expression and drug sensitivity in AML and implicates HBE inhibition as a novel cuproptosis trigger.

cancer biology↗

bioRxiv2023

Cell Type-Specific Regulation by a Heptad of Transcription Factors in Human Hematopoietic Stem and Progenitor Cells

Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay of transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs - FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2 - bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remained unknown. We mapped genome-wide chromatin contacts and TF binding profiles in HSPC subsets (HSC, CMP, GMP, MEP) and found that heptad occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. These findings suggest that specific heptad-TF combinations play critical roles in regulating hematopoietic differentiation and provide a valuable resource for development of targeted therapies to manipulate specific HSPC subsets.

developmental biology↗