Anguera Lab Post #2 – Isabel Sierra, Graduate Student

January 23, 2020

Hey Isabel here, I’m a third year PhD student in the CAMB/DSRB graduate program. In the Anguera lab we are especially interested in dosage compensation, a mechanism to balance the gene expression of the X chromosome between females and males. But why and how is dosage compensation achieved?

Typically chromosomes are identical between females and males, except when it comes to the sex chromosomes. Differences in sex chromosome composition can result in an imbalance of gene expression. For example, in mammals the X chromosome has a larger contribution of gene expression than the Y. Therefore, females who have two Xs (XX) have an added challenge of regulating double the X-linked gene dosage compared to males who have one (XY). Fortunately, nature has come up with an elegant system to address this problem. All placental mammals (XX/XY) equalize gene expression through X-Chromosome Inactivation (XCI), an epigenetic process to transcriptionally silence one of the female X chromosomes. Proper dosage compensation is critical for female development and must be maintained in every somatic cell to prevent overexpression of X-linked genes commonly seen in autoimmune diseases such as Systemic Lupus Erythematosus. Between different placental mammalian species there are minor differences in how XCI is initiated and maintained, however all species rely on the long non-coding RNA XIST to achieve XCI. Surprisingly, the closely related marsupial (like the kangaroo) also inactivates a single female X chromosome, but does not rely on the long non-coding RNA XIST to achieve dosage compensation in this system.

Outside of mammals, other organisms also face the challenge of unequal gene expression from the sex chromosomes. In flies, such as the popular model organism Drosophila melanogaster, the sex chromosomes are similar to mammals in that females are XX and males are XY. However, flies achieve dosage compensation through a completely different mechanism. In this system it is the male fly which alters its gene expression, doubling the expression of their single X to equalize to the female XX expression. Another interesting example of the variety in dosage compensation mechanisms can be seen in the worm Caenorhabditis elegans. In these worms females are XX while males are XO. The female worms downregulate each of their X chromosomes by half to compensate for the single male X.

I find it amazing how dosage compensation mechanisms have evolved so differently to solve the same basic problem. This underscores the absolute importance of maintaining strict control over X-linked gene expression. As a graduate student in the Anguera lab, my goal for my thesis is to better understand how dosage compensation and XCI is maintained, and how disruption of this process could lead to female-biased disease susceptibility. I am very excited to delve deeper into studying the epigenetic mechanisms regulating XCI.