Further Development 14.2: X Chromosome Inactivation

The inactivation of one of the two X-chromosomes in a female mammal appears to be accomplished by placing the DNA of one of the two X chromosomes into heterochromatin. This heterochromatin remains condensed throughout most of the cell cycle and replicates later than most of the other chromatin (the euchromatin) of the nucleus. The heterochromatic (inactive) X chromosome, which can often be seen on the nuclear envelope of female cells, is referred to as a Barr body (FIGURE 14.14A; Barr and Bertram 1949). By monitoring the expression of X-linked genes whose products can be detected in the early embryo, we learned that X-chromosome inactivation occurs early in development. (FIGURE 14.14B,C). This inactivation appears to be critical. Using a mutant X chromosome that could not be inactivated, Tagaki and Abe (1990) showed that the expression of two X chromosomes per cell in mouse embryos leads to ectodermal cell death and the absence of mesoderm formation, eventually causing embryonic death at day 10 of gestation.

Based on her studies on mouse coat colors, an observable X-linked trait, Mary Lyon (1961) proposed the following hypothesis to account for these results:

  1. Very early in the development of female mammals, both X chromosomes are active.
  2. As development proceeds, one X chromosome is inactivated in each cell.
  3. This inactivation is random. In some cells, the paternally derived X chromosome is inactivated; in other cells, the maternally derived X chromosome is shut down.
  4. This process is irreversible. Once an X chromosome has been inactivated in a cell, the same X chromosome is inactivated in all that cell’s progeny. Since X inactivation happens relatively early in development, an entire region of cells derived from a single cell may all have the same X chromosome inactivated. Thus, all tissues in female mammals are mosaics of two cell types.

Each woman is therefore a “mosaic” where some cells have their father’s X chromosome active, and other cells have their mothers X chromosome active (FIGURE 14.14D). The heterogeneity of metabolism in the two different cell types (and the ability of one cell type to provide nutrients to the other) may lead to women being healthier and more long-lived than men, having a 20% lower death rate at every post-implantation stage of the life cycle until after age 75 (when there are many more women in the population) (Kristiansen et al. 2005; Migeon 2020).

X-chromosome inactivation does not extend to every gene on the X chromosome nor to every cell type. Carrel and Willard (2005) estimate that about 15 percent of the genes on the X chromosome escape inactivation. Persistence of X-chromosome inactivation holds true only for somatic cells, not germ cells. In female germ cells, the inactive X chromosome is reactivated after mitosis expands their population shortly before the cells enter meiosis (Gartler et al. 1973; Migeon and Jelalian 1977).

Although the result is the same, the mechanisms of human X-chromosome inactivation differ from those of the mouse (Migeon 2001 2002; Patrat et al. 2020). The major determinant for X-chromosome inactivation is a long non-coding RNA called XIST. XIST RNA is initially made by both X-chromosomes, but it is retained only by one of them. The XIST RNA is thought to bind proteins that remodel nucleosomes and methylate the DNA, thereby suppressing transcription (Zylicz et al. 2019). Based on X-chromosome inactivation in aneuploid cells, Migeon (2021) has hypothesized that a protein encoded on the short arm of chromosome 19 blocks XIST transcription and thereby “protects” one of the X chromosomes from being inactivated. But it only makes enough protein to protect one X, but not two. In rare embryos with trisomic sex chromosomes (47 chromosomes, including XXX and XXY) embryos, only one X chromosome is active; but in complete triploid embryos (with 69 chromosomes, including XXX or XXY sex chromosomes), two X chromosomes are active (Migeon et al. 2008). In this manner, the dosage of gene products from the X-chromosome becomes generally equalized in men and women.

References:

Barr, M. L., & Bertram, E. G. 1949. A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature 163, 676– 677. doi:10.1038/163676a0

Carrel, L., Willard, H.2005. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404. https://doi.org/10.1038/nature03479

Kristiansen M, Knudsen GP, Bathum L, Naumova AK, Sørensen TI, Brix TH, Svendsen AJ, Christensen K, Kyvik KO, Ørstavik KH. 2005. Twin study of genetic and aging effects on X chromosome inactivation. Eur J Hum 13: 599-606.

Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373

Migeon BR 2020. X-linked diseases: susceptible females.  Genet Med. 22: 1156-1174. doi: 10.1038/s41436-020-0779-4.

Migeon BR. 2021. Stochastic gene expression and chromosome interactions in protecting the human active X from silencing by XIST.  Nucleus 12(1):1-5. doi: 10.1080/19491034.2020.1850981.

Migeon, B. R. and K. Jelalian. 1977. Evidence for two active X chromosomes in germ cells of female before meiotic entry. Nature 269: 242–243.

Patrat C, Ouimette JF, Rougeulle C. X chromosome inactivation in human development. Development. 2020 Jan 3;147(1):dev183095. doi: 10.1242/dev.183095

Tagaki, N. and K. Abe. 1990. Detrimental effects of two active X chromosomes on early mouse development. Development 109: 189–201.

Zylicz, J. J., Bousard, A., Zumer, K., Dossin, F., Mohammad, E., da Rocha, S. T., Schwalb, B., Syx, L., Dingli, F., Loew, D. et al. (2019). The implication of early chromatin changes in X chromosome inactivation. Cell 176: 182-197.

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