Biology subjects

Wang, H.-L. V.

Publications and source records attributed to Wang, H.-L. V..

3 recordsLinked to original sources

bioRxiv2025

Temporal regulation of human reactive astrocytes reveals their capacity for antigen presentation

Astrocytes adapt to injury and disease by entering a reactive state defined by transcriptomic, morphological, and functional changes. Using a combination of human cortical organoids (hCOs) and primary fetal brain tissue, we investigated the plasticity of human astrocyte reactivity. We observed robust inflammatory transcriptomic and chromatin signatures following cytokine exposure, which varied with duration. To assess reversibility, we withdrew cytokines after acute or chronic exposure. In both cases, astrocytes returned to a quiescent genomic state within days. Chronic exposure induced MHC class II gene expression, normally restricted to professional antigen-presenting cells. We validated MHCII protein in primary tissue and hCOs and used co-immunoprecipitation and mass spectrometry to identify candidate antigens. Finally, we showed that exogenous peptides from fetal neurons could be presented by astrocytic MHCII.

neuroscience↗

bioRxiv2023

Single nucleus multiome analysis of the prefrontal cortex from C9orf72 ALS/FTD patients illuminates pathways affected during disease progression

Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development. Loss of neurosurveillance microglia and activation of the complement cascade take place early, when pTDP-43 aggregates are absent or very low, and become more pronounced in late stages, suggesting an initial involvement of microglia in disease progression. Reduction of layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 also occurs early, and the reduction becomes more pronounced as pTDP-43 accumulates. Several unique features were observed only in samples with high levels of pTDP-43, including global alteration of chromatin accessibility in oligodendrocytes, microglia, and astrocytes; higher ratios of premature oligodendrocytes; increased levels of the noncoding RNA NEAT1 in astrocytes and neurons, and higher amount of phosphorylated ribosomal protein S6. Our findings reveal previously unknown progressive functional changes in major cell types found in the frontal cortex of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.

neuroscience↗

bioRxiv2020

Transgenerational inheritance of BPA-induced obesity correlates with transmission of new CTCF sites in the Fto gene

Transgenerational transmission of epiphenotypes is poorly understood. Here we show that exposure of pregnant mouse F0 females to BPA results in obesity in the F2 progeny due to increased food intake and leptin resistance. This epiphenotype can be transmitted up to the F6 generation and disappears in F7. Analyses of chromatin accessibility in sperm of the F1-F6 generations reveals alterations in the binding of CTCF at two enhancers of the Fto gene in obese but not control animals that correlates with transmission of obesity. Deletion of the CTCF site in Fto results in mice that fail to become obese when exposed to BPA. These Fto enhancers show increased interactions in sperm of obese mice with the Irx3 and Irx5 genes, which are involved in the differentiation of appetite controlling AgRP/NPY neurons. Single-nucleus and immunofluorescence analyses in the arcuate nucleus of the hypothalamus suggest that exposure to BPA results in expansion of the number of orexigenic AgRP neurons. This expansion correlates with increased accessibility of the Fto proximal enhancer in radial glia-like neural stem cells (RG-NSCs), which give rise to AgRP/NPY neurons, and in mature oligodendrocytes. The results provide a molecular mechanism for transgenerational inheritance in mammals and suggest that both genetic and epigenetic alterations of Fto can lead to the same phenotypic outcomes.

genomics↗