Biology subjects

Lau, X.

Publications and source records attributed to Lau, X..

3 recordsLinked to original sources

bioRxiv2025

Cumulative pregnancy and postnatal environmental exposures impact social behaviour in male mice associated with epigenetic, ribosomal, and immune dysregulation

Environmental exposures across critical developmental windows can significantly influence brain development and contribute to the pathogenesis of neurodevelopmental disorders (NDDs). Emerging clinical evidence suggests that cumulative environmental factors during early development result in more pronounced disease phenotypes in offspring. Here, we developed a triple-hit model using C57Bl/6JAusb mice to examine the cumulative effects of antenatal social stress, antenatal chronic high-fat diet consumption, and postnatal poly(I:C) exposure on neurodevelopmental outcomes in offspring. Male triple-hit offspring displayed autism-like social deficits and an overall increased susceptibility to neurodevelopmental behavioural alterations in adulthood compared to male non-stressed controls. Conversely, these behavioural changes were not observed amongst female triple-hit offspring. Single-cell RNA (scRNA) transcriptomic and bulk proteomic sequencing were performed in male triple-hit offspring across peripheral blood immune cells and brain tissue. scRNA sequencing in microglia, astrocytes, and oligodendrocytes revealed dysregulation in critical glial cell processes, ribosomal functions, and chromatin remodelling. Similar functional themes were observed across peripheral blood macrophages, neutrophils, and naive B cells - displaying immune and ribosomal dysregulation at the transcriptional level. Proteomics pathway enrichment analyses revealed significantly reduced protein abundance in ribosomal biogenesis, translation, and chromatin remodelling functions in both peripheral blood immune cells and brain tissue. We also observed synaptic dysfunction in the blood and brain proteome. Overall, using our unique triple-hit model, we demonstrate that multiple early life environmental exposures drive NDD-associated behaviours in a sex-specific manner; and is associated with overlapping central and peripheral molecular mechanisms that have clinical relevance to NDD pathogenesis.

developmental biology↗

bioRxiv2024

Spatial transcriptomic profiling of human retinoblastoma

Retinoblastoma (RB) represents one of the most prevalent intraocular cancers in children. Understanding the tumor heterogeneity in RB is important to design better targeted therapies. Here we used spatial transcriptomic to profile human retina and RB tumor to comprehensively dissect the spatial cell-cell communication networks. We found high intratumoral heterogeneity in RB, consisting of 10 transcriptionally distinct subpopulations with varying levels of proliferation capacity. Our results uncovered a complex architecture of the tumor microenvironment that predominantly consisted of cone precursors, as well as glial cells and cancer-associated fibroblasts. We delineated the cell trajectory underlying malignant progression of RB, and identified key signaling pathways driving genetic regulation across RB progression. We also explored the signaling pathways mediating cell-cell communications in RB subpopulations, and mapped the spatial networks of RB subpopulations and region neighbors. Altogether, we constructed the first spatial gene atlas for RB, which allowed us to characterize the transcriptomic landscape in spatially-resolved RB subpopulations, providing novel insights into the complex spatial communications involved in RB progression.

systems biology↗

bioRxiv2023

Single cell RNA-seq reveals protracted germ line X chromosome reactivation dynamics directed by a PRC2 dependent mechanism

Initiating soon after PGC specification, female germ cells undergo reactivation of the silenced X chromosome during genome wide reprogramming. However, the kinetics and dynamics of XCR in vivo have remained poorly understood. To address this here we perform a global appraisal of XCR using high-dimensional techniques. Using F1 B6 v CAST mouse embryos, we perform a detailed assessment, applying single-cell RNA-seq and chromatin profiling on germ cells purified from E10.5 to E16.5. While scRNA-seq profile showed that male and female germ cells are transcriptionally indistinct at E11.5, they are sexually dimorphic by E12.5, diverging further through development to E16.5. With allelic resolution, we show that the reactivating X chromosome is only partly active at E10.5, then reactivates gradually and reaches near parity in output to the constitutively active X chromosome at [~]E16.5 when developing oogonia are meiosis prophase I. Crucially, we show that sexually dimorphic dosage compensation patterns observed in germ cells, occur in tandem with an increase in the allelic proportion from the reactivating X chromosome. While Xist is extinguished from E10.5, the epigenetic memory of earlier XCI in female cells persists much longer, likely from self-sustained PRC2 complex (Ezh2 / Eed / Suz12) function. The reactivating X chromosome is enriched in the epigenetic silencing mark H3K27me3 at E13.5, which is removed by E16.5 permitting gene expression. Our findings link XCR, along with functional regulation of PRC2 in promoting female meiosis.

developmental biology↗