Biology subjects

Khor, J.

Publications and source records attributed to Khor, J..

5 recordsLinked to original sources

bioRxiv2025

Very long-chain ceramides in muscle associate with insulin resistance independent of obesity

Lipids, in particular ceramides and diacylglycerols (DAGs), are implicated in insulin resistance, however their precise roles remain unclear. We leverage natural genetic variation to examine muscle lipids and systemic insulin resistance (IR) in 399 Diversity Outbred Australia mice. Adipose mass was associated with 55% of muscle lipids and IR, with DAGs as the only enriched lipid class. To disentangle adiposity and muscle lipid contributions, we used two approaches: (1) linear modelling of muscle lipids corrected for adipose mass on systemic IR, and (2) stratifying mice into insulin sensitivity quartiles within adiposity bins. Both revealed that very long-chain ceramides, but not DAGs, were linked to IR. Transcriptomic and proteomics further associated these ceramides with cellular and mitochondrial stress. DAGs correlated with leptin expression in muscle, suggesting they originate from muscle-residing adipocytes. We propose that many muscle lipids, including DAGs, associate with IR due to adipose accumulation rather than directly influencing muscle insulin sensitivity. By addressing the relationship between adiposity and metabolic state, we identified very long-chain muscle ceramides as highly associated with IR independently of adiposity.

systems biology↗

bioRxiv2025

Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma

Chemotherapy often kills a large fraction of cancer cells but leaves behind a small population of drug- tolerant persister cells. These persister cells survive drug treatments through reversible, non-genetic mechanisms and cause tumour recurrence upon cessation of therapy. Here, we report a drug tolerance mechanism regulated by the germ-cell-specific H3K4 methyltransferase PRDM9. Through histone proteomic, transcriptomic, lipidomic, and ChIP-sequencing studies combined with CRISPR knockout and phenotypic drug screen, we identified that chemotherapy-induced PRDM9 upregulation promotes metabolic rewiring in glioblastoma stem cells, leading to chemotherapy tolerance. Mechanistically, PRDM9-dependent H3K4me3 at cholesterol biosynthesis genes enhances cholesterol biosynthesis, which persister cells rely on to maintain homeostasis under chemotherapy- induced oxidative stress and lipid peroxidation. PRDM9 inhibition, combined with chemotherapy, resulted in strong anti-cancer efficacy in preclinical glioblastoma models, significantly enhancing the magnitude and duration of the antitumor response by eliminating persisters. These findings demonstrate a previously unknown role of PRDM9 in promoting metabolic reprogramming that enables the survival of drug-tolerant persister cells.

cancer biology↗

bioRxiv2024

Identification of phenotypic and transcriptomic signatures underpinning maize crown root systems

Maize is pivotal in supporting global agriculture and addressing food security challenges. Crop root systems are critical for water uptake and nutrient acquisition, which impacts yield. Quantitative trait phenotyping is essential to understand better the genetic factors underpinning maize root growth and development. Root systems are challenging to phenotype given their below-ground, soil-bound nature. In addition, manual trait annotations of root images are tedious and can lead to inaccuracies and inconsistencies between individuals, resulting in data discrepancies. To address these issues, we have developed an automated phenotyping pipeline for field-grown maize crown roots by leveraging open-source software. Phenotypic variation of 20 maize genotypes from the Wisconsin Diversity panel was significant for numerous root traits, suggesting a genetic basis for the observed developmental deviations. In addition, juvenile root traits from controlled environment conditions exhibited inconsistent correlation with field-grown adult root traits, underscoring the developmental plasticity prevalent during maize root morphogenesis. Transcripts involved in hormone signaling and stress responses were among differentially expressed genes in roots from 20 maize genotypes, suggesting many molecular processes may underlie the observed phenotypic variance. This study furthers our understanding of genotype-phenotype relationships, which is relevant for informing agricultural strategies to improve maize root physiology.

plant biology↗

bioRxiv2023

The Auxin Response Factor ARF27 is required for maize root morphogenesis

Crop root systems are central to nutrition acquisition and water usage. Root hairs and lateral roots contribute to fine-scale patterning of root systems and can offer many advantages for improving root function without drastically impacting overall system architecture. Key genetic regulators underpinning root hair morphogenesis have been well characterized in the model plant Arabidopsis but are less understood in maize. Here, we identify a novel determinant of root hair morphogenesis and auxin responses in maize, AUXIN RESPONSE FACTOR27 (ARF27), using both reverse and quantitative genetic approaches. ARF27 is enriched in maize primary root tissues at both the transcript and protein level. Loss of ARF27 leads to short primary roots and reduced root hair formation, while lateral root density is unaltered. In arf27 roots, auxin-responsive gene expression is dysregulated, which is consistent with the predicted function of this transcription factor. Moreover, a genome wide association study (GWAS) to uncover genetic determinants of auxin-dependent root traits identified ARF27 as a candidate gene. Furthermore, auxin hypersensitive maize genotypes exhibit altered crown root length and surface area in field-grown plants. A gene regulatory network (GRN) was reconstructed and an ARF27 subnetwork was integrated with DAP-seq and GWAS data to identify ARF27 target genes. The ARF27 GRN includes known maize root development genes, such as ROOTLESS CONCERNING CROWN ROOTS (RTCS), ROOTHAIRLESS 3 (RTH3) and RTH6. Altogether this work identifies a novel genetic driver of auxin-mediated root morphogenesis in maize that can inform agricultural strategies for improved crop performance.

plant biology↗

bioRxiv2023

ZmPILS6 is an auxin efflux carrier required for maize root morphogenesis

Plant root systems play a pivotal role in plant physiology and exhibit diverse phenotypic traits. Understanding the genetic mechanisms governing root growth and development in model plants like maize is crucial for enhancing crop resilience to drought and nutrient limitations. This study focused on identifying and characterizing ZmPILS6, an annotated auxin efflux carrier, as a key regulator of various crown root traits in maize. ZmPILS6-modified roots displayed reduced network area and suppressed lateral root formation, desirable traits during drought and low phosphate conditions. The research revealed that ZmPILS6 localizes to the endoplasmic reticulum and plays a vital role in controlling the spatial distribution of indole-3-acetic acid (IAA or "auxin") in primary roots. The study also demonstrated that ZmPILS6 can actively efflux IAA when expressed in yeast. Furthermore, the loss of ZmPILS6 resulted in significant proteome remodeling in maize roots, particularly affecting hormone signaling pathways. To identify potential interacting partners of ZmPILS6, a weighted gene co-expression analysis (WGNA) was performed. Altogether, this research contributes to the growing knowledge of essential genetic determinants governing maize root morphogenesis, which is crucial for guiding agricultural improvement strategies. Significance StatementCrop yield and stress resilience are significantly influenced by crown root architecture. A reverse genetic screen aimed at identifying novel regulators of maize root morphogenesis led to the discovery of ZmPILS6, an auxin efflux carrier. The loss of ZmPILS6 negatively impacts numerous root traits that are linked to plant physiology and function. Proteomic characterization of pils6-1 roots revealed that this evolutionarily conserved transporter is required for the proper expression of numerous phytohormone pathways, including abscisic acid, gibberellins, and jasmonic acid. Notably, ZmPILS6 appears to have a contrasting role in regulating root morphogenesis compared to its Arabidopsis ortholog, PILS6. This finding emphasizes the need for functional characterization of candidate genes directly within key crops of interest, which cannot always be correctly inferred from other model plants.

plant biology↗