Genome complexity: picking one X chromosome per cell (Introduction)

by David Turell , Monday, March 15, 2021, 18:11 (1135 days ago) @ David Turell

A new study:

https://phys.org/news/2021-03-reveals-clues-architecture-chromosomes.html

"To prevent both X chromosomes from being active, female mammals have a mechanism that inactivates one of them during development. X chromosome inactivation is orchestrated by a noncoding form of RNA called Xist, which silences genes by spreading across the chromosome, recruiting other proteins (such as Polycomb repressive complexes) to complete the task.

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"In this study, Lee and Andrea Kriz, a Ph.D. student and first author of the paper, were interested in understanding the role of clusters of proteins called cohesins in X inactivation. Cohesins are known to play a critical role in gene expression. Imagine a chromosome as a long piece of string with genes and their regulatory sequences being far apart, says Lee. For the gene to be turned "on" and do its job, such as producing a specific protein, it has to come in contact with its distant regulator. Chromosomes allow this to happen by forming a small loop that brings together the gene and regulator. Ring-shaped cohesins help these loops form and stabilize. When the gene's work is done and it's time to turn off, a scissor-like protein called WAPL snips it, causing the gene to disconnect from its regulator. An active chromosome has many of these loops, which are continually forming and dissociating (or separating).

"These small loops, which are essential for gene expression, are relatively suppressed on an inactivated X chromosome. One reason, as Lee and her colleagues have already shown, is that Xist "evicts" most cohesins from the inactive X chromosome and that this cohesin depletion may be necessary to reorganize the shape and structure of the chromosome for silencing.

"In the current study, Lee and Kriz used embryonic stem cells from female mice to find out what happens when cohesin or WAPL levels are manipulated during X chromosome inactivation by using protein-degradation technology. "We found that if cohesin levels build up too high, the X chromosome cannot inactivate properly," says Lee. Normally, retaining cohesins (which are normally supposed to be evicted) prevented the X chromosome from folding into an inactive shape and gene silencing was affected. "You need a fine balance between eviction and retention of cohesins during X chromosome inactivation," says Lee.

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"These findings suggests that shape and structure of the X chromosome play a vital role in allowing Xist to spread from one side to the other and achieve inactivation. "The more we learn about what's important for silencing the X chromosome," says Lee, "the more likely we'll be to find ways to reactivate it and to treat conditions like Rett syndrome.'"

Comment: Probably cohesins are managed by a feedback loop. When sexual reproduction appeared, the necessity of silencing one x chromosome is obvious. It had to be provided at the same time for success, so simultaneous design is a requirement.