Biology subjects

Taylor-Papadimitriou, J.

Publications and source records attributed to Taylor-Papadimitriou, J..

3 recordsLinked to original sources

bioRxiv2024

Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling

Loss-of-function mutations in genes encoding lysine methyltransferases (KMTs) and demethylases (KDMs) responsible for regulating the trimethylation of histone 3 on lysine 4 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder and intellectual disability. To study the specific role of H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex. These included elevated expression of Grin2d. The Grin2d gene product NMDAR2D was increased in synaptosomes isolated from the Kdm5b-deficient neocortex and treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalisations and reduced repetitive digging behaviours. These findings suggest that increased H3K4me3 levels and associated Grin2d gene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency. TeaserInhibitors targeting NMDA receptors may represent viable therapies for KDM5B neurodevelopmental disorders

neuroscience↗

bioRxiv2020

Cancer-associated hypersialylated MUC1 drives the differentiation of monocytes into macrophages with a pathogenic phenotype

The tumour microenvironment plays a crucial role in the growth and progression of cancer and the presence of tumour-associated macrophages (TAMs) is associated with poor prognosis. Recent studies show that TAMs show transcriptomic, phenotypic, functional and geographical diversity. Here we show that a sialylated tumour-associated glycoform of the mucin MUC1, MUC1-ST, through the engagement of Siglec-9 can specifically and independently induce the differentiation of monocytes into TAMs with a unique phenotype. These TAMs can recruit and maintain neutrophils, inhibit the function of T cells, degrade basement membrane allowing for invasion, are inefficient at phagocytosis, and can induce plasma clotting. This novel macrophage phenotype is enriched in the stroma at the edge of breast cancer nests and their presence is associated with poor prognosis in breast cancer patients.

cancer biology↗

bioRxiv2019

O-linked mucin-type glycosylation regulates the transcriptional programme downstream of EGFR in breast cancer

Aberrant mucin type O-linked glycosylation is a common occurrence in cancer. This type of O-linked glycosylation is not limited to mucins but can occur on many cell surface glycoproteins where only a small number of sites may be present. Upon EGF ligation, EGFR induces a signaling cascade but can also translocate to the nucleus where it can directly regulate gene transcription. Here we show that upon EGF binding, human breast cancer cells carrying different O-linked glycans respond by transcribing different gene expression signatures. This is not a result of changes in signal transduction but due to the differential nuclear translocation of EGFR in the two glyco-phenotypes. This is regulated by the formation of an EGFR/galectin-3/MUC1/{beta}-catenin complex at the cell surface that is present in cells carrying short core-1-based O-glycans characteristic of tumour cells but absent in core-2-carrying cells.

cancer biology↗