[ad_1]
By Brian Aguado, College of California San Diego
Most mammals, together with people, have two intercourse chromosomes, X and Y. One intercourse chromosome is often inherited from every father or mother, and so they pair up as both XX or XY in each cell of the physique. Individuals with XX chromosomes usually establish as feminine, and other people with XY chromosomes usually establish as male. The genes on these chromosomes play a key position in improvement and performance – together with how coronary heart illness develops.
Earlier than I grew to become a biomedical engineer finding out how intercourse chromosomes have an effect on the center, I realized about one curious operate of X chromosomes in my highschool science class, with the calico cat instance.
Feminine calico cats nearly at all times have orange and black splotches of fur, as a result of the gene that defines coat coloration is discovered on the X chromosome. When an orange cat mates with a black cat, feminine offspring, which generally inherit one X chromosome from every father or mother, may have a mix of orange and black fur – one X chromosome encodes for orange fur whereas the opposite encodes for black fur. For that reason, male cats, which generally have one X and one Y chromosome, have stable orange or black coats.
Calico and tortoiseshell cats have multicolored patches of fur as a result of solely one in all their two X chromosomes is activated in every cell.
How does this intercourse distinction in fur coloration occur biologically? Because it seems, cells with XX chromosomes expertise X-inactivation: The X chromosome from one father or mother is turned off in some cells, whereas the X chromosome inherited from the opposite father or mother is turned off in others. Within the cells of feminine calico cats, X-inactivation can result in splotches of orange and black fur if one X chromosome comes from a father or mother with orange fur and the opposite X chromosome comes from a father or mother with black fur.
X-inactivation occurs as a result of organisms like cats and other people want just one X chromosome to operate correctly. To make sure the proper “dosage,” one of many X chromosomes is turned off in each cell. However among the genes on the inactivated X chromosome escape inactivation and keep turned on. Actually, as much as one-third of the genes on the X chromosome in individuals can escape inactivation, and they’re thought to play a job in regulating well being and illness.
As a result of X-inactivation occurs solely in these individuals with multiple X chromosome, researchers like me have been taking a look at how the genes that escape inactivation on the second X have an effect on the well being of individuals with XX chromosomes. We’ve discovered that for sure situations, cell intercourse could also be on the coronary heart of the matter.
A change of coronary heart
One illness that X chromosome escape genes partially regulate is aortic valve stenosis, a situation wherein the a part of the center that controls blood stream to the remainder of the physique stiffens and narrows. This makes the center work tougher to pump blood and may in the end result in coronary heart failure. Very similar to an individual attempting to push open a door with rusty hinges, the center will get drained. There are at the moment no efficient medication out there to sluggish or halt AVS illness signs.
Hearts with aortic valve stenosis should pump tougher to push blood by a narrowed aortic valve to the remainder of the physique.
SuneErichsen/Wikimedia Commons, CC BY-SA
My lab research how intercourse chromosomes can have an effect on cardiovascular situations like AVS. Earlier research have proven that the valves of individuals with XX versus XY chromosomes can stiffen in numerous methods. Usually, individuals with XX chromosomes have elevated scarring, known as fibrosis, whereas individuals with XY chromosomes have elevated calcium deposits. Given these variations, I suspected that giving the identical drug to everybody won’t be the easiest way to deal with AVS. However what could possibly be inflicting these variations?
By and huge, researchers suppose intercourse hormones drive intercourse variations in valve tissue stiffening. Certainly, lowering estrogen ranges throughout menopause can exacerbate coronary heart fibrosis. Nonetheless, research on heart problems in XX and XY mice have discovered that intercourse variations nonetheless persist even after surgically excising the reproductive organs that produce intercourse hormones.
My workforce and I hypothesized that the genes that escape X-inactivation, being distinctive to individuals with XX chromosomes, could also be driving these variations in valve stiffening. To check this concept, we developed bioengineered fashions of valve tissue utilizing hydrogels. Hydrogels mimic the stiffness of valve tissue higher than the standard petri dish medium, permitting us to review coronary heart cells in an surroundings that extra carefully resembles the physique.
Coronary heart tissue with XX chromosomes has the next focus of cells (coloured inexperienced, with blue nuclei) that promote scarring than do cells with XY chromosomes.
Brian Aguado, CC BY-NC-ND
We discovered that the cells we grew on our hydrogel fashions have been capable of replicate the intercourse variations seen in valve tissue – specifically, valve cells with XX chromosomes had extra scarring than cells with XY chromosomes. Furthermore, after we decreased the exercise of genes that escaped X-inactivation, we have been capable of lower scarring in XX chromosome cells.
Our subsequent step was to make use of our fashions to find out which therapies work finest for AVS primarily based on cell intercourse. We discovered that XX valve cells have been much less delicate than XY cells to those medication that focused genes that promote scarring. Medicine that particularly goal genes that escape X-inactivation, nonetheless, have a stronger impact on XX cells.
[ad_2]
