Down syndrome results from the triplication of chromosome 21 and is a leading cause of intellectual disability. However, Down syndrome is also a model for accelerated aging. A fresh find from Li-Huei Tsai’s group (Massachusetts Institute of Technology) not only uncovers molecular mechanisms that may explain some of the resulting dysfunction but also offers a potential therapeutic path through senolytics – that is, drugs that induce death in senescent cells.
In neural progenitors with trisomy 21, they found disruptions to nuclear architecture towards chromosomal introversion (more interactions within a chromosome, fewer with other chromosomes), which are characterized by:
- Decreases in trans-chromosomal interactions (assessed using Hi-C)
- Reorganized topologically association domains (TADs), with most having higher intra-TAD interaction densities in the inactive compartment of the genome within the nucleus
- Differential chromosomal looping – with more loops in TADs with increased density
- Decreased lamina-associated protein LMNB1 and increased nuclear H3K9me3 suggests disrupted nuclear lamina (assessed using immunofluorescence)
- Reduced LMNB1 association in TADs with increased intrachromosomal interactions (ChIP-Seq)
- Transcriptional upregulation is associated with this introversion (RNA-Seq); downregulation is associated with disrupted chromatin accessibility (ATAC-Seq)
- Signatures of cellular senescence
- Increased number of senescent cells (senescence-associated β-galactosidase staining)
- High correlation of differentially expressed genes and those following oxidative stress-induced senescence (RNA-Seq)
Hinting at the fountain of youth, the molecular and cellular dysfunction is ameliorated by the senolytic drugs dasatinib and quercetin (DQ).
First author Hiruy Meharena shares, “There is a cell-type specific genome-wide disruption that is independent of the gene dosage response. It’s a very similar phenomenon to what’s observed in senescence. This suggests that excessive senescence in the developing brain induced by the third copy of chromosome 21 could be a key reason for the neurodevelopmental abnormalities seen in Down syndrome.”
Senior author Li-Huei Tsai adds, “This study illustrates the importance of asking fundamental questions about the underlying mechanisms of neurological disorders. We didn’t begin this work expecting to see senescence as a translationally relevant feature of Down syndrome, but the data emerged from asking how the presence of an extra chromosome affects the architecture of all of a cell’s chromosomes during development.”
Peer down the path of senescence in Cell Stem Cell, January 2022.