Biology subjects

Taggart, J.

Publications and source records attributed to Taggart, J..

5 recordsLinked to original sources

bioRxiv2025

Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation

Somatic mutations that increase hematopoietic stem cell (HSC) fitness drive their expansion in clonal hematopoiesis (CH) and predispose to blood cancers. Although CH frequently occurs with aging, it rarely progresses to overt malignancy. Population variation in the growth rate and potential of mutant clones suggests the presence of genetic factors protecting against CH, but these remain largely undefined. Here, we identify a non-coding regulatory variant, rs17834140-T, that significantly protects against CH and myeloid malignancies by downregulating HSC-selective expression and function of the RNA-binding protein MSI2. By modeling variant effects and mapping MSI2 binding targets, we uncover an RNA network that maintains human HSCs and influences CH risk. Importantly, rs17834140-T is associated with slower CH expansion rates in humans, and stem cell MSI2 levels modify ASXL1-mutant HSC clonal dominance in experimental models. These findings leverage natural resilience to highlight a key role for post-transcriptional regulation in human HSCs, and offer genetic evidence supporting inhibition of MSI2 or its downstream targets as rational strategies for blood cancer prevention.

genetics↗

bioRxiv2025

The interactome of the Bakers' yeast peroxiredoxin Tsa1 implicates it in the redox regulation of intermediary metabolism, glycolysis and zinc homeostasis

Zinc (Zn) is an essential nutrient supporting a range of critical processes. In the yeast Saccharomyces cerevisiae, Zn deficiency induces a transcriptional response mediated by the Zap1 activator, which controls a regulon of [~]80 genes. A subset support zinc homeostasis by promoting zinc uptake and its distribution between compartments, while the remainder mediate an "adaptive response" to enhance fitness of zinc deficient cells. The peroxiredoxin Tsa1 is a Zap1-regulated adaptive factor essential for the growth of Zn deficient cells. Tsa1 can function as an antioxidant peroxidase, protein chaperone, or redox sensor: the latter activity oxidizes associated proteins via a redox relay mechanism. We previously reported that in Zn deficient cells, Tsa1 inhibits pyruvate kinase (Pyk1) to conserve phosphoenolpyruvate for aromatic amino acid synthesis. However, this regulation makes a relatively minor contribution to fitness in low zinc, suggesting that Tsa1 targets other pathways important to adaptation. Consistent with this model, the redox sensor function of Tsa1 was essential for growth of ZnD cells. Using an MBP-tagged version of Tsa1, we identified a redox-sensitive non-covalent interaction with Pyk1, and applied this system to identify multiple novel interacting partners. This interactome implicates Tsa1 in the regulation of critical processes including many Zn-dependent metabolic pathways. Interestingly, Zap1 was a preferred Tsa1 target, as Tsa1 strongly promoted the oxidation of Zap1 activation domain 2, and was essential for full Zap1 activity. Our findings reveal a novel posttranslational response to Zn deficiency, overlain on and interconnected with the Zap1-mediated transcriptional response. Graphical abstractIn ZnD cells, Tsa1 mediates metabolic adaptation by regulation of glycolytic enzymes Pyk1 and Fba1, and supports activity of the Zap1 transcriptional activator via oxidation of the AD2 domain. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/638137v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1ef6858org.highwire.dtl.DTLVardef@ab9682org.highwire.dtl.DTLVardef@12644a3org.highwire.dtl.DTLVardef@1644fe0_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

A high-resolution view of RNA endonuclease cleavage in Bacillus subtilis

RNA endonucleases are the rate-limiting initiator of decay for many bacterial mRNAs. However, the positions of cleavage and their sequence determinants remain elusive even for the well-studied Bacillus subtilis. Here we present two complementary approaches - transcriptome-wide mapping of endoribonucleolytic activity and deep mutational scanning of RNA cleavage sites - that reveal distinct rules governing the specificity among B. subtilis endoribonucleases. Detection of RNA terminal nucleotides in both 5'- and 3'-exonuclease-deficient cells revealed >103 putative endonucleolytic cleavage sites with single-nucleotide resolution. We found a surprisingly weak consensus for RNase Y targets, a contrastingly strong primary sequence motif for EndoA targets, and long-range intramolecular secondary structures for RNase III targets. Deep mutational analysis of RNase Y cleavage sites showed that the specificity is governed by many disjointed sequence features, each with mild contributions. Our results highlight the delocalized nature of mRNA stability determinants and provide a strategy for elucidating endoribonuclease specificity in vivo.

molecular biology↗

bioRxiv2020

Linking scales of life-history variation with population structure in Atlantic cod

It is increasing recognised that sustainable exploitation of marine fish requires the consideration of population diversity and associated productivity. This study used a combination of genotypic screening and phenotypic traits to define the scale of population structuring in Atlantic cod inhabiting the northern North Sea (ICES 4a) and Scottish west coast (6a). The genetic analysis indicated an isolation by distance pattern with an even finer scale structuring than previously reported, that persisted over a decade and between feeding and spawning seasons. Spatial variation in phenotypic traits reflected genetic variation with cod maturing later and at a larger size near the Viking Bank in 4a. The identified population structuring provides an explanation for differences in historic changes in maturation schedules and the temperature exposure recorded in previous electronic tagging studies. The study also highlights how the mismatch between stock divisions and population units is leading to a misunderstanding about stock recovery.

ecology↗

bioRxiv2018

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

The MUSASHI family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We found that the small molecule Ro 08-2750 (Ro) directly binds to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells resulted in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrated in vivo inhibition of c-MYC and reduced disease burden in a murine AML leukemia model. Thus, we have identified a small molecule that targets MSIs oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

cancer biology↗