Mammals achieve dosage compensation by the transcriptional inactivation of one of the two X chromosomes in female somatic cells, a process known as X-inactivation. As a result of X-inactivation, two X chromosomes can coexist within the same nucleus, exposed to the same diffusible transcription regulators, yet differ entirely in their expression.
Early in the development of a female embryo, when it consists of a few hundred cells, one of the two X chromosomes in each cell becomes highly condensed into a type of heterochromatin. The initial choice of which X chromosome to inactivate, the maternally inherited one (Xm) or the paternally inherited one (Xp), is random. Once either Xp or Xm has been inactivated, it remains silent throughout all subsequent cell divisions of that cell and its progeny, indicating that the inactive state is faithfully maintained through many cycles of DNA replication and mitosis. Because X-inactivation is random and takes place after several hundred cells have already formed in the embryo, every female is a mosaic of clonal groups of cells in which either Xp or Xm is silenced (Figure 7–50). These clonal groups are
Xp Xm Xp Xm Xp Xm CONDENSATION OF A RANDOMLY SELECTED X CHROMOSOME DIRECT INHERITANCE OF THE PATTERN OF CHROMOSOME CONDENSATION DIRECT INHERITANCE OF THE PATTERN OF CHROMOSOME CONDENSATION Figure 7–50 X-inactivation. the clonal inheritance in female mammals of a only Xm active in this clone only Xp active in this clone condensed, inactive X chromosome.
Figure 7–51 Photoreceptor cells in the retina of a female mouse showing patterns of X-chromosome inactivation. Using genetic engineering techniques (described in Chapter 8), the germ line of a mouse was modified so that one copy of the X chromosome (if active) makes a green fluorescent protein and the other a red fluorescent protein. Both proteins concentrate in the nucleus and, in the field of cells shown here, it is clear that only one of the two X chromosomes is active in each cell. (from h. wu et al., Neuron 81:103–119, 2014. with permission from elsevier.) distributed in small clusters in the adult animal because sister cells tend to remain close together during later stages of development (Figure 7–51). For example, X-chromosome inactivation causes the orange and black “tortoiseshell” coat coloration of some female cats. In these cats, one X chromosome carries a gene that produces orange hair color, and the other X chromosome carries an allele of the same gene that results in black hair color; it is the random X-inactivation that produces patches of cells of two distinctive colors. In contrast, male cats of this genetic stock are either solid orange or solid black, depending on which X chromosome they inherit from their mothers. Although X-chromosome inactivation is maintained over thousands of cell divisions, it is reversed during germ-cell formation, so that all haploid oocytes contain an active X chromosome and can express X-linked gene products.
How is an entire chromosome transcriptionally inactivated? X-chromosome inactivation is initiated and spreads from a single site near the middle of the X chromosome, the X-inactivation center (XIC). Within the XIC is a transcribed 20,000-nucleotide lncRNA (called Xist), which is expressed solely from the inactive X chromosome. Xist RNA spreads from the XIC over the entire chromosome and directs gene silencing. Although we do not know exactly how this is accomplished, it likely involves recruitment of histone-modifying enzymes and other proteins to form a repressive form of chromatin analogous to that of Figure 7–45. Curiously, about 10% of the genes on the X chromosome (including Xist itself) escape this silencing and remain active.