February 8, 2021
12pm (noon) - 1pm
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Hiruy Sibhatu Meharena, PhD
Massachusetts Institute of Technology (MIT)
"Genomic Imbalance and 3D-Genome Organization in Intellectual Disability"
Genomic imbalances, including aneuploidies and copy number variants (CNVs), are one of the leading causes of intellectual disabilities such as Down syndrome (DS) and Autism Spectrum Disorder (ASD). Rare mutations that disrupt the 3D-genome organization have also been associated with intellectual disability. While these disorders display similar clinical features, the molecular mechanisms underlying this convergence remains unclear. We find that neural progenitors harboring trisomy 21, an aneuploidy that leads to DS, exhibit global 3D-genome reorganization, disruption of the nuclear lamina, and genome-wide chromatin accessibility changes. These features resemble the genome-wide transcriptional and nuclear-architecture changes that are characteristic of senescent cells. Moreover, we find that an ASD-associated mutation in CTCF induces a transcriptional profile similar to those observed in neural progenitors derived from individuals with DS, indicating that there is a molecular mechanism convergence between aneuploidies and chromosomal looping disruptions. Additionally, we find that treatment of neural progenitors harboring trisomy 21 with anti-senescence drugs (senolytics) alleviates the transcriptional and cellular changes associated with the neurodevelopmental malformations observed in individuals with DS. Our findings indicate that senescence plays a key role in the neurodevelopmental pathogenesis of DS and pharmacologically targeting senescence may provide a novel therapeutic avenue for treating individuals with DS.
Live virtual zoom – Seminar
Host: Dr. Alvaro Sagasti