Biology subjects

Kassim, B.

Publications and source records attributed to Kassim, B..

4 recordsLinked to original sources

bioRxiv2022

HIV integration in the human brain is linked to microglial activation and 3D genome remodeling

Exploration of genome organization and function in the HIV infected brain is critical to aid in the development of treatments for HIV-associated neurocognitive disorder (HAND) and HIV cure strategies. Here, we generated a resource comprised of single nuclei transcriptomics, complemented by cell-type-specific Hi-C chromosomal conformation ( 3D genome) and viral integration site sequencing (IS-seq) in frontal brain tissues from individuals with HIV encephalitis (HIVE), HIV-infected people without encephalitis (HIV+), and HIV uninfected (HIV-) controls. We observed profound 3D genomic reorganization of open/repressive (A/B) compartment structures encompassing 6.4% of the HIVE microglial genome that was associated with transcriptomic reprogramming, including down-regulation of homeostasis and synapse-related functions and robust activation of interferon signaling and cell migratory pathways. HIV RNA was detected in 0.003% of all nuclei in HIVE brain, predominantly in the most activated microglia where it ranked as the second most highly expressed transcript. Microglia from HIV+ brains showed, to a lesser extent, similar transcriptional alterations. IS-seq recovered 1,221 insertion events in glial nuclei that were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Brain and peripheral myeloid cell integration revealed a preference overall for transcription-permissive chromatin, but robust differences in the frequency of recurrent insertions, intergenic integration, and enrichment for pre-integration complex-associated factors at integration sites. Our resource highlights critical differences in the genomic patterns of HIV infection in brain versus blood and points to a dynamic interrelationship between inflammation-associated 3D genome remodeling and successful integration in brain.

neuroscience↗

bioRxiv2021

NEURON-SPECIFIC CHROMOSOMAL MEGADOMAIN ORGANIZATION IS ADAPTIVE TO RECENT RETROTRANSPOSON EXPANSIONS

Here, we mapped cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B2NeuN+ megabase-scaling subcompartment. Comparative chromosomal conformation mapping in Mus spretus and Mus musculus revealed neuron-specific reconfigurations tracking recent ERV2 retrotransposon expansions in the murine germline, with significantly higher B2 megadomain contact frequencies at sites with ongoing ERV2 insertions in Mus musculus. Ablation of the retrotransposon silencer Kmt1e/Setdb1 triggered B2 megadomain disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly of ERV2/Intracisternal-A-Particles (IAPs) infiltrating dendrites and spines. We conclude that neuronal megadomain architectures include evolutionarily adaptive heterochromatic organization which, upon perturbation, unleashes ERV proviruses with strong tropism within mature neurons.

neuroscience↗

bioRxiv2020

Common genetic variation in humans impacts in vitro susceptibility to SARS-CoV-2 infection

The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant inter-individual variability. In addition to showing more disease in males, the elderly, and individuals with underlying co-morbidities, SARS-CoV-2 can seemingly render healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants also impact vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR-engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single nucleotide polymorphism (rs4702), common in the population at large, and located in the 3UTR of the protease FURIN, impacts alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can impact viral infection, and thus contribute to clinical heterogeneity in SARS-CoV-2. Ongoing genetic studies will help to better identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs that might treat disease.

cell biology↗

bioRxiv2020

Neuronal and glial 3D chromatin architecture illustrates cellular etiology of brain disorders

Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks. Here we integrated genome-wide chromosome conformation in purified neurons and glia with transcriptomic and enhancer profiles to build the gene regulatory landscape of two major cell classes in the human brain. Within glutamatergic and GABAergic neurons, we were able to link enhancers to their cognate genes via neuronal chromatin interaction profiles. These cell-type-specific regulatory landscapes were then leveraged to gain insight into the cellular etiology of several brain disorders. We found that Alzheimers disease (AD)-associated epigenetic dysregulation was linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia as a central cell type, suggesting that different cell types may confer risk to the disease via different genetic mechanisms. Moreover, neuronal subtype-specific annotation of genetic risk factors for schizophrenia and bipolar disorder identified shared (parvalbumin-expressing interneurons) and distinct cellular etiology (upper layer neurons for bipolar and deeper layer projection neurons for schizophrenia) between these two closely related psychiatric illnesses. Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.

neuroscience↗