“Genomic Imbalance and 3D-Genome Organization in Intellectual Disability”
Hosted by the Department of Genetics
Abstract: Abstract: Genomic Imbalance which includes aneuploidies and copy number
variants (CNVs) are one of the leading causes of intellectual disability, which
includes Down syndrome (DS) and Autism Spectrum Disorder (ASD).
Additionally, 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, which leads to Down syndrome, exhibit global 3D-genome
reorganization, disruption of the nuclear lamina, and genome-wide chromatin
accessibility changes. The genome-wide transcriptional and nucleararchitecture changes observed in trisomy 21 harboring neural progenitors are
characteristic hallmarks of senescent cells. We find that treatment of trisomy
21 harboring neural progenitors with senolytic (anti-senescence) drugs
alleviates the transcriptional and cellular changes associated trisomy 21.
Additionally, we find that an ASD associated mutation on the 3D-genome
organizing gene, CTCF, induces a transcriptional profile similar to those
observed in neural progenitors derived from individuals with Down syndrome,
indicating that neural progenitor senescence maybe a cellular hallmark of
intellectual disabilities. In conclusion, our findings indicate that senescence
plays a key role in neurodevelopmental disorders associated with intellectual
disabilities and pharmacologically targeting senescence provides an exciting
therapeutic avenue for treating individuals with DS and other intellectual
disabilities caused by genomic imbalance.
For inquiries contact Debbie Peterson.