Biology subjects

Mechawar, N.

Publications and source records attributed to Mechawar, N..

39 records · Page 3Linked to original sources

bioRxiv2018

Non-CG methylation and multiple epigenetic layers associate child abuse with immune and small GTPase dysregulation

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we described molecular cross-talk among multiple epigenetic mechanisms, including 6 histone marks, DNA methylation and the transcriptome, in subjects with a history of ELA and controls. We first uncovered, in the healthy brain, previously unknown interactions among epigenetic layers, in particular related to non-CG methylation in the CAC context. We then showed that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicated that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides new insights into epigenetic brain regulation as a function of early-life experience.

neuroscience↗

bioRxiv2018

MIC-MAC: High-throughput analysis of three-dimensional microglia morphology in mammalian brains

Microglia, the resident immune cells of the brain, exhibit complex and diverse phenotypes depending on their physiological context including brain regions and disease states. While single-cell RNA-sequencing has recently resolved this heterogeneity, it does not capture tissue and intercellular mechanisms. Our complementary imaging-based approach enables automatic 3D-morphology characterization and classification of thousands of individual microglia in situ and revealed species- and disease-specific morphological phenotypes in mouse and human brain samples.

neuroscience↗

bioRxiv2018

Single-nucleus RNA sequencing shows convergent evidence from different cell types for altered synaptic plasticity in major depressive disorder.

Major depressive disorder (MDD) is a complex illness that involves the interaction of different brain systems, pathways, and cell types. Past molecular studies of MDD relied on cellular homogenates of post-mortem brain tissue, making it impossible to determine gene expression changes within individual cells. Using single-cell transcriptomics, we examined almost 80,000 nuclei from the dorsolateral prefrontal cortex of individuals with MDD and healthy controls. Our analyses identified 26 distinct cellular clusters, and over 60% of these showed transcriptional differences between groups. Specifically, 96 genes were differentially expressed, the majority of which were downregulated. Convergent evidence from our analyses, including gene expression, differential correlation, and gene ontology implicated dysregulation of synaptic plasticity in the etiopathogenesis of MDD. Our results show that this high-resolution approach can reveal previously undetectable changes in specific cell types in the context of complex phenotypes and heterogeneous tissues.

neuroscience↗