In Down syndrome cells, genome-wide disruptions mimic a senescence-like
state

Date:
January 6, 2022
Source:
Picower Institute at MIT
Summary:
Extra chromosome alters chromosomal conformation and DNA
accessibility across the whole genome in neural progenitor cells,
disrupting gene transcription and cell functions much like in
cellular aging.



FULL STORY ==========================================================================
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, a new study shows. The resulting disruption of gene transcription and cell function are so similar to those seen in cellular
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 Cell Stem Cell therefore establishes senescence as
a potentially targetable mechanism for future treatment of Down syndrome,
said Hiruy Meharena, a new assistant professor at the University of
California San Diego who led the work as a Senior Alana Fellow in the
Alana Down Syndrome Center at MIT.

"There is a cell-type specific genome-wide disruption that is independent
of the gene dosage response," Meharena said. "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." 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, said senior author
Li-Huei Tsai, but it is substantiated by the team's extensive work to
elucidate the underlying mechanism of the effects of abnormal chromosome number, or aneupoloidy, within the nucleus of the 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 of
The Picower Institute for Learning and Memory at MIT. "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." Genomewide changes Meharena and co-authors spent years measuring distinctions between human cell cultures
that differed only by whether they had a third copy of chromosome 21.

Stem cells derived from volunteers were cultured to turn into NPCs. In
both the stem cells and the NPCs, the team examined 3D chromosome
architecture, several metrics of DNA structure and interaction, gene accessibility and transcription, and gene expression. They also looked at
the consequences of the gene expression differences on important functions
of these developmental cells, such as how well they proliferated and
migrated in 3D brain tissue cultures.

Stem cells were not particularly different, but NPCs were substantially affected by the third copy of chromosome 21.



========================================================================== Overall, the picture that emerged in NPCs was that the presence of a
third copy causes all the other chromosomes to squish inward, not unlike
when people in a crowded elevator must narrow their stance when one more
person squeezes in. The main effects of this "chromosomal introversion," meticulously quantified in the study, are more genetic interactions
within each chromosome and less interactions among them. These changes
and differences in DNA conformation within the cell nucleus lead to
changes in how genes are transcribed and therefore expressed, causing
important differences in cell function that affect brain development.

Treated as senescence For the first couple of years as these data
emerged, Meharena said, the full significance of the genomic changes
were not apparent, but then he read a paper showing very similar genomic rearrangement and transcriptional alterations in senescent cells.

After validating that the Down syndrome cells indeed bore such a similar signature of transcriptional differences, the team decided to test whether anti-senolytic drugs could undo the effects. They tested a combination
of two: dasatinib and quercetin. The medications improved not only gene accessibility and transcription, but also the migration and proliferation
of cells.

That said, the drugs have very significant side effects -- dasatinib
is only given to cancer patients when other treatments have not done
enough -- so they are not appropriate for attempting to intervene in
brain development amid Down syndrome, Meharena said. Instead an outcome
of the study could be to inspire a search for medications that could
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-directed
the Alana Center with Tsai, has shown that aneuploidy is a source of considerable stress for cells. A question raised by the new findings, therefore, is whether the senescence-like character of Down syndrome
NPCs is indeed the result of an aneuploidy induced stress and if so,
exactly what that stress is.

Another implication of the findings is how excessive senescence among
brain cells might affect people with Down syndrome later in life. The
risk of Alzheimer's disease is much higher at a substantially earlier age
in the Down syndrome population than among people in general. In large
part this is believed to be because a key Alzheimer's risk gene, APP,
is on chromosome 21, but the newly identified inclination for senescence
may also accelerate Alzheimer's development.

The Alana Foundation, the LuMind Foundation, Burroughs Wellcome Fund,
UNCF- Merck and the National Institutes of Health funded the research.

special promotion Explore the latest scientific research on sleep and
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Content may be edited for style and length.


========================================================================== Journal Reference:
1. 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, Li-Huei Tsai. Down-syndrome-induced senescence disrupts
the nuclear architecture of neural progenitors. Cell Stem Cell,
2022; 29 (1): 116 DOI: 10.1016/j.stem.2021.12.002 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220106111555.htm

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