Biology subjects

Balic, J.

Publications and source records attributed to Balic, J..

3 recordsLinked to original sources

bioRxiv2026

Genome-wide characterization of extant clonal diversity in Chilean Carmenere

Carmenere is a widely cultivated and internationally recognized grapevine cultivar in Chile, yet genetic variation among its clones remains poorly characterized. Early studies based on SSR and AFLP markers detected limited polymorphism, but these approaches interrogate only a small fraction of the genome, leaving the extent of clonal diversity unresolved. Here, we generated an improved chromosome-scale diploid genome assembly of Carmenere FPS clone 02 and characterized clonal genomic diversity by sequencing 36 biological replicates representing 12 clones maintained in Chile, including heritage selections rescued from old producer vineyards by Vina Santa Carolina as part of its Bloque Herencia conservation program, and commercial nursery-derived clones. Focusing on low-frequency variants and using replicate-aware consensus calling, we identified more than 9,000 private single nucleotide variants (SNVs) and small indels per clone, providing high-resolution markers for clonal identification. Although most variants were located in repetitive or intergenic regions, a subset affected coding sequences, with genes involved in plant-pathogen interactions, transport, and secondary metabolism most frequently impacted. While variant-affected genes associated with wine anthocyanin content, TA, pH, and alcohol percentage were identified, broader phenotypic characterization will be required to assess their biological significance. Overall, this study provides a genome-wide characterization of extant clonal diversity in Carmenere, with implications for clonal selection and genetic resource conservation.

genomics↗

bioRxiv2024

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia

Understanding the molecular pathogenesis of MLL fusion oncoprotein (MLL-FP) leukaemia has spawned epigenetic therapies that have improved clinical outcomes in this often-incurable disease. Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in MLL-FP leukaemia. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate the MLL-FP transcriptional program. Inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of MLL-FP. Consequently, combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Moreover, PF-9363 or genetic depletion of KAT7 can also overcome acquired genetic/non-genetic resistance to Menin inhibition. These data provide the molecular rationale for rapid clinical translation of combination therapy in MLL-FP leukaemia.

cancer biology↗

bioRxiv2020

STAT3 Serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression

Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor (TLR)-4 expressed on macrophages induces a robust pro-inflammatory response which has recently been shown to be dependent on metabolic reprogramming 1, 2, 3, 4. These innate metabolic changes have been compared to the Warburg effect (also known as aerobic glycolysis) described in tumour cells 5, 6. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming remain unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show both ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, the production of the central immune-metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.

immunology↗