In Down syndrome, the third copy of chromosome 21 causes a reorganization of the 3D configuration of the entire genome in a key cell type of the developing brain, according to a new study. The resulting disruptions in gene transcription and cell function are so similar to those seen in cell aging, or senescence, that the scientists leading the study found they could use anti-senescence drugs. to correct them in cell cultures.
The study published in Stem cell therefore establishes senescence as a potentially targeted mechanism for future treatment of Down syndrome, said Hiruy Meharena, a new assistant professor at the University of California at San Diego who led the work as Senior Alana Fellow at Alana Down Syndrome. MIT Center.
âThere is a cell-type specific genome-wide disturbance that is independent of the gene assay response,â Meharena said. “This is a very similar phenomenon to what is seen in senescence. It 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 the syndrome. Down. “
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 new, said lead author Li-Huei Tsai , but it is supported by the team’s extensive work to elucidate the mechanism underlying the effects of an abnormal number of chromosomes, or aneupoloidism, in the nucleus of cells.
“This study illustrates the importance of asking fundamental questions about the underlying mechanisms of neurological disorders,” said 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 hoping to see senescence as a translational relevant feature of Down syndrome, but data emerged from the question of how the presence of an extra chromosome affects the architecture of all chromosomes in a cell during development. “
Meharena and her co-authors spent years measuring the distinctions between cultures of human cells that differed only in whether or not they had a third copy of chromosome 21. Stem cells derived from volunteers were grown for turn into an NPC. In stem cells and NPCs, the team looked at 3D chromosomal architecture, several measures of DNA structure and interaction, gene accessibility and transcription, and gene expression. They also examined the consequences of differences in gene expression on important functions of these developmental cells, such as how they proliferated and migrated in 3D brain tissue cultures. Stem cells weren’t particularly different, but NPCs were significantly affected by the third copy of chromosome 21.
Overall, the image that emerged in NPCs was that the presence of a third copy causes all other chromosomes to crash inward, much like when people in a crowded elevator have to shrink their legs. position when one more person is in a hurry. The main effects of this meticulously quantified âchromosome introversion,â in the study, are more genetic interactions within each chromosome and fewer interactions between them. These changes and differences in the conformation of DNA within the cell nucleus lead to changes in the way genes are transcribed and therefore expressed, causing important differences in cell function that affect brain development.
Treated like senescence
During the first two years that this data emerged, Meharena said, the full significance of the genomic changes was not apparent, but he then read an article showing a very similar genomic rearrangement and transcriptional alterations in senescent cells.
After validating that Down syndrome cells did carry a similar signature of transcriptional differences, the team decided to test whether anti-senolytic drugs could negate the effects. They tested a combination of two: dasatinib and quercetin. The drugs improved not only the accessibility and transcription of genes, but also the migration and proliferation of cells.
That said, the drugs have some very serious side effects – dasatinib is only given to cancer patients when other treatments have not done enough – so they are not suitable for attempting to intervene in development. brain in the middle of Down syndrome, Meharena said. Instead, a result of the study might be to inspire research for drugs that might have anti-senolytic effects with a safer profile.
Senescence is a stress response of cells. At the same time, years of research by former MIT biology professor Angelika Amon, who co-led the Alana Center with Tsai, has shown that aneuploidy is a source of considerable stress on cells. A question raised by the new findings is therefore whether the senescence-like character of NPCs with Down’s syndrome is indeed the result of stress induced by aneuploidy and if so, what exactly is this 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 disease is much higher at a significantly younger age in the population with Down’s 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 found on chromosome 21, but the newly identified tendency to senescence may also accelerate the development of Alzheimer’s disease. .
The Alana Foundation, the LuMind Foundation, the Burroughs Wellcome Fund, UNCF-Merck, and the National Institutes of Health funded the research.