An extra chromosome changes the chromosomal conformation and DNA
In Down syndrome, the third copy of chromosome 21 causes a rearrangement of the 3D configuration of the entire genome in a key developing brain cell type, according to a new study. The resulting disruption of gene transcription and cellular function is so similar to that seen in cellular aging, or senescence, that the scientists leading the study found they could use anti-aging drugs. -senescence to correct them in cell cultures.
The study published in Cell Stem Cell therefore establishes senescence as a potentially targetable mechanism for the future treatment of Down syndrome, says Hiruy Meharena, who led the work as a Senior Alana Fellow at the Alana Down Syndrome Center at MIT and is now an assistant professor at the University of California, San Diego.
“There is a cell type-specific genome-wide disruption that is independent of the gene dosage response,” Meharena says. “It’s a phenomenon very similar to what we observe 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.
The study’s finding that neural progenitor cells (NPCs), which develop into major cells in the brain, including neurons, have a senescent character is remarkable and novel, says lead author Li-Huei Tsai, but it is underpinned by the team’s extensive work to elucidate the mechanism underlying the effects of abnormal chromosome number, or aneupoloidy, in the nucleus of cells.
“This study illustrates the importance of asking fundamental questions about the underlying mechanisms of neurological disorders,” says Tsai, Picower Professor of Neuroscience, director of the Alana Center and the Picower Institute for Learning and Memory at MIT. “We did not begin this work expecting to see senescence as a translationally relevant feature of Down syndrome, but data emerged asking how the presence of an extra chromosome affects the architecture of all the chromosomes of a cell during development.”
Meharena and his co-authors spent years measuring the distinctions between cultures of human cells that differed only in having a third copy of chromosome 21. Stem cells derived from volunteers were cultured to transform in NPC. In stem cells and NPCs, the team examined 3D chromosomal architecture, several DNA structure and interaction parameters, gene accessibility and transcription, and gene expression. They also examined the consequences of gene expression differences on important functions of these developmental cells, such as their ability to proliferate and migrate in 3D brain tissue cultures. The stem cells weren’t particularly different, but the NPCs were significantly affected by the third copy of chromosome 21.
Overall, the picture that emerged among NPCs was that the presence of a third copy causes all other chromosomes to be squashed inward, much like when people in a crowded elevator have to shrink their position when one more person sneaks up. The main effects of this “chromosomal introversion”, meticulously quantified in the study, are more genetic interactions within each chromosome and fewer interactions between them. These changes and differences in DNA conformation within the cell nucleus lead to changes in the way genes are transcribed and therefore expressed, causing important differences in cellular function that affect brain development.
Treated as senescence
For the first two years this data emerged, Meharena says, the full significance of the genomic changes was not apparent, but then he read a paper showing very similar genomic rearrangement and transcriptional alterations in senescent cells.
After validating that Down syndrome cells did indeed carry such a similar signature of transcriptional differences, the team decided to test whether anti-senescence drugs could reverse the effects. They tested a combination of the two: dasatinib and quercetin. The drugs not only improved gene accessibility and transcription, but also cell migration and proliferation.
That said, the drugs have some very serious side effects – dasatinib is only given to cancer patients when other treatments haven’t done enough – so they’re not appropriate for trying to intervene in brain development in the first place. middle of Down syndrome, says Meharena. Instead, one outcome of the study could be to inspire a search for drugs that may have anti-senolytic effects with a safer profile.
Senescence is a stress response of cells. At the same time, years of research by the late MIT biology professor Angelika Amon, who co-directed the Alana Center with Tsai, has shown that aneuploidy is a significant source of stress for cells. A question raised by the new findings, therefore, is whether the senescence-like character of NPCs with Down syndrome is indeed the result of aneuploidy-induced stress, and if so, what exactly is that stress.
Another implication of the findings is how excessive brain cell senescence might affect people with Down syndrome later in life. The risk of Alzheimer’s the disease is much higher at a significantly earlier age in the population with Down syndrome than among people in general. This is thought to be largely due to the fact that a key Alzheimer’s risk gene, APP, is on chromosome 21, but the newly identified tendency towards senescence may also accelerate the development of Alzheimer’s disease. .
Reference: “Down’s syndrome-induced senescence disrupts the nuclear architecture of neural progenitors” by Hiruy S. Meharena, Asaf Marco, Vishnu Dileep, Elana R. Lockshin, Grace Y. Akatsu, James Mullahoo, L. Ashley Watson, Tak Ko, Lindsey N. Guerin, Fatema Abdurrob, Shruthi Rengarajan, Malvina Papanastasiou, Jacob D. Jaffe and Li-Huei Tsai, January 6, 2022, Cell Stem Cell.
Besides Meharena and Tsai, the other authors of the article are Asaf Marco, Vishnu Dileep, Elana Lockshin, Grace Akatsu, James Mullahoo, Ashley Watson, Tak Ko, Lindsey Guerin, Fatema Abdurrob, Shruti Rengarajan, Malvina Papanastasiou and Jacob Jaffe.
The Alana Foundation, LuMind Foundation, Burroughs Wellcome Fund, UNCF-Merck, and the National Institutes of Health funded the research.