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New model for Down’s Syndrome Developed Using X Chromosome Inactivation

I have a special cousin who has Down’s syndrome. He’s cheerful. He’s kind. He’s hardworking, He has a photo collage of all his extended family in his room. We all love him dearly. I admire my aunt who dutifully raised him, with the same discipline as her other healthy son. Unfortunately, Down’s syndrome produces an additional challenge, as my cousin ages…memory loss from Alzheimer’s disease.

That is why I am so grateful to researchers like Jeanne Lawrence of Umass Medical school in Worcester Massachusetts.  Last week her group published this impressive article Jun Jiang et al. Nature Translating dosage compensation to trisomy 21. (2013) Nature. Their notable comment was “Our hope is that for individuals and families living with Down’s syndrome, the proof-of-principle demonstrated here initiates multiple new avenues of translational relevance for the 50 years of advances in basic X-chromosome biology.”


To understand this paper, you need to understand dosage compensation. This epigenetic regulatory system prevents twice the expression of all the X chromosome genes in females. It works like this. The gene XIST expresses non-coding RNA that randomly targets one of the X chromosomes in each cell during blastocytosis. The silence is stabilized by hypermethylation of promoter CpG islands. The chromosome is condensed, forming what is termed a “barr body”. Interestingly, around 10% of the genes in the barr body somehow escape inactivation. It has been known for some time that inactivation spreads linearly along the X chromosome. We also knew that a non-sex chromosome can be attached in the lab to an X chromosome undergoing inactivation, so that it too will be silenced. The inactivated X chromosome or Barr body is only reactivated as an X chromosome during oocyte formation. That way both sets of the potential grandparents’ X chromosome can be available for inheritance.  In cases of women with Triple X, or three X chromosomes two of the three X chromosomes will be silenced.  So there must be some feedback mechanism protecting one.

The basic cause of Down’s syndrome is the extra copy of chromosome 21. The researchers asked, “Would the XIST mechanism work on that extra copy?” The answer was yes.


This cell culture model was designed thoughtfully to be useful in basic research as ‘trisomy correction in a dish’. Inducible doxycycline-controlled XIST transgene was inserted into chromosome 21, of Down’s syndrome iPS cells, via zinc finger nuclease (ZFN)-driven targeted addition. One to all three copies of chr 21 could take in XIST.  Impressive enough, since such a large gene has not been inserted by this method before. Heterochromatic epigenetic marks, such as histone post translational modifications, were used to show whole chromosome silencing similar to barr bodies. They also showed 100% silencing of various individual chromosome 21 genes, i.e. RNA FISH. Including the gene that encodes β-amyloid precursor protein, that is over expressed in Down’s characteristc Alzheimer’s.


However in any of their cultured clonal lines, they observed that other epigenetic adaption processes work to silence the inserted XIST genes over time. Or otherwise the XIST gene is just lost by cells. XIST repression had an additional “defined effect on the genomic expression profile, and reverses deficits in cell proliferation and neural progenitors, which has implications for hypocellularity in the Down’s syndrome brain”.  Cells likely have measures in place to ensure correct overall dosage from a pair of non-sex chromosomes.

Since X chromosome dosage is so stable, I wonder what other mechanisms are at work?  What do iPS cells in this model have in common with cells undergoing oocyte formation?


Excitingly, the authors point out that their findings are a boost to future translational research and gene therapy research. Parallel cultures can be compared for differences in genome-wide pathways and Down’s syndrome related cell pathologies. The model iPS cells can be differentiated, i.e. neurons for studies. Hopefully someday therapies could be even be developed for Down’s adults, or could treat Down’s syndrome in utero. I’m just going to say it. The ideas from these researchers are mind blowing.

This entry was posted in Cell Culture Models, Cellular Biology, Developmental Biology, Imaging, Neuroscience, New Lab Methods, Stem Cells and tagged , , , , . Bookmark the permalink.

One Response to New model for Down’s Syndrome Developed Using X Chromosome Inactivation

  1. prof premraj pushpakaran says:

    2014 is the 50th year of X-chromosome inactivation research. Mary Lyon’s pioneer work is laudable!!!

    prof premraj pushpakaran

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