Although it sometimes feels like there is no right way to age, intriguing insight from Down Syndrome has given insight into how disrupted nuclear architecture can push us down the wrong path.
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.