X chromosome inactivation in human cells

Published on March 31, 2010 Reviewed on June 29, 2016   48 min

Other Talks in the Series: Epigenetics

0:00
I am Barbara Migeon, a member of the McKusick Nathans Institute of Genetic Medicine at Johns Hopkins. The title of my talk is X Chromosome Inactivation in Human Cell.
0:15
I will talk to you about X chromosome inactivation, the way mammals carry out X dosage compensation. This has been the subject of previous talks by Mary Lyon and Jenny Graves. Although we hear a lot about how the mouse inactivates one X chromosome, I will be talking about the version of X chromosome inactivation in our own species. First I will tell you what we know from studies of human cells and human subjects. Then I will talk about how inactivating human X chromosomes differ from the process in other species and what might be responsible for such differences. And last, changing the focus from inactive to active X, I will tell you why diploid human cells have only a single active X, no matter the number of Xs in the cell and how this active X is chosen.
1:17
Most studies of the early events in X inactivation have been carried out in mice as it's been difficult to look at human embryos at that time. However, the study of humans has other advantages. Our phenotype is understood better than that of any other organism and we can learn a good deal from the study of cultured cell. Also one X chromosome can be isolated from the other in hybrid cell. Spontaneous abortions provide a wealth of X chromosome deletions and different numbers of X chromosome. And now we have begun to study human ES cells, embryonic stem cells and cleaving embryos left over from in vitro fertilization. We can also transfect human genes into mice for developmental study. Furthermore, the fact that humans are not inbred and are in fact very heterozygous for many X-linked genes has enabled studies less feasible in other mammal. Females are indeed a genetic mosaic as you see here, with some cells expressing the genes from their paternal X, and others, the genes from the maternal one.
2:41
X inactivation is the way that all placental and pouched mammals carry out X dosage compensation. However, while the basic mechanisms seem to be similar, there are differences in the detail. What I would like to emphasize in my talk are the variations on the theme of X inactivation. You should not be surprised to learn that mammals vary a lot in the details of X inactivation. The molecular biologist Francois Jacob said it best when he pointed out that evolution was a tinkerer. I took the liberty of summarizing what he said rather poetically. "Evolution behaves like a tinkerer who slowly modifies his work, cutting here, lengthening there to adapt it progressively to its new use. But unlike engineers, tinkerers who tackle the same problem are likely to end up with different solutions."
3:48
You can see the evidence of such tinkering in the various mechanisms of X dosage compensation used by organisms who have a sex difference in the number of X chromosome. We know empirically that when one sex has a single X and the other has two Xs, the species does not survive unless one of the sexes undergoes dosage compensation. In all cases, the dose of X-linked genes is equalized between males and females by modulating the transcriptional output of the X chromosome. Yet how this is accomplished differs from one species to another. Here you see how it is done in flies, worms, and mammals. The modified X chromosome is colored yellow. Flies compensate by increasing the transcription of the male X so that it equals the output of the two Xs in the female. Worms decrease the transcription of both female X chromosomes so that they equal the output of the single male X. And mammals and only mammals turn off the transcription of one of the two X chromosomes in each cell. Note that there are at least three different ways to accomplish sex dosage compensation and all of them are used.
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X chromosome inactivation in human cells

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