• John Rinn

X chromosome 'mega domain' regulates autosomes!

The X chromosome has fascinated biologists for decades. The X chromosome faces a dilemma that there are two copies in some people and one in others. So when there are two XX chromosomes the cell needs to turn off one them -- to keep things similar to single X chromosome cells. The 'mega domain' is a unique way the X chromosome folds inside the cell's nucleus to accomplish this process and only occurs in XX cells. One way to think about the mega-domain is the linear chromosome forming a pretzel -- where the ends fold in on the center looping out the regions in between -- like a chromosomal pretzel.

The 'mega domain' is such a cool discovery and could explain how the cell chooses which X chromosome to turn off in XX cells. Moreover, it's highly conserved across mammalian species -- meaning the cell found a common way to do this from mice to humans. Thus, it would appear the DNA sequence encoding the elements that form the 'mega-domain' -- the parts that make the pretzel -- are the key factors.

Here we decided to genetically remove the center of the pretzel and see what happens. We chose to do this in an animal model system to determine the physiological relevance on a organismal scale. Previous studies used a similar approach in stem cells found the cells were fine -- but what about a multi-cellular living animal like a mouse?

To tackle this it required a heroic effort between two postdoctoral scholars Daniel Andergassen and Zach Smith in Ale

xander Meissner's lab. They took it a step further by using two different types -- or strains -- of mice so they could determine which X was which. Especially in the XX cells we needed to know which X had the mega-domain and which did not. Also we could examine different stages of animal development where the mega-domain may play roles. For example, in the placenta XX specifically have to turn off the X that came from the father -- supposedly so the mother doesn't recognize the baby as foreign and cause an immune response. Thanks to CRISPR-CAS9 engineering they were able to make dozens of mouse models required to dissect each part of the pretzel.

Surprisingly after we deleted hundreds of thousands of letters from the X chromosome sequence -- everybody was happy and healthy, XX and XY alike! What -- how could this be taking away so much highly conserved DNA and nothing? So they looked further and found that the X chromosome itself was behaving normal despite these large truncations. Even on a molecular level the animals did not seem to mind missing so much of their X chromosome. So they dug even deeper and looked around the rest of the genome.

Eureka! The cells were responding to the missing pieces of the pretzel, it just wasn't coming from the damaged X chromosome -- it was the other chromosomes that were unhappy. Woah -- so how does the X chromosome communicate with the other chromosomes to make them unhappy? Answer : more genetics. So Zach and Daniel further determined which of the three parts (center and two ends that come together) of the pretzel was talking to the other chromosomes. Two of three parts are termed DXZ4 (center) and FIRRE (end) -- the names are not important. What they found is that FIRRE alone even when removed in combination with DXZ4 was causing the non X chromosomes to be unhappy. Perhaps they got cold in the absence of FIRRE :)

By way of analogy, the X chromosome seems to be the queen bee of the nucleus. If the queen sends out distress signals then the rest of the bees respond to help. How in the world this communication works on a molecular level will be of great interest in future studies.

In the meantime here is a short slide-cast summarizing the study in eLife.

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