The spread of Xist RNA along the X chromosome does not proceed linearly along the DNA. Rather, starting at its site of synthesis, it is first handed off across the base of the DNA loops that make up the chromosome; these shortcuts explain how Xist can spread rapidly, by a “hand-over-hand” mechanism, along the X chromosome once the inactivation process begins (Figure 7–52). It also helps to explain why the inactivation does not spread to the other, active X chromosome.
Imprinting and X-chromosome inactivation are examples of monoallelic gene expression, where in a diploid genome, only one of the two copies of a gene is expressed. In addition to the approximately 1000 genes on the X chromosome and the 300 or so genes that are imprinted, there are another 1000–2000 human genes that exhibit monoallelic expression. Like X-chromosome inactivation (but unlike imprinting), the choice of which copy of the gene is to be expressed and which is to be silenced often appears random. Yet once the choice is made, it can persist for many cell divisions. Because the choice is often made relatively late in development, cells of the same tissue in the same individual can express different copies of a given gene. In other words, somatic tissues are often mosaics, where different clones of cells have subtly different patterns of gene expression. The mechanisms responsible for this type of monoallelic expression are not known in detail, and its general purpose—if any—is poorly understood. Several different mechanisms may contribute to such epigenetic inheritance, as we explain next.
epigenetic Mechanisms ensure that Stable patterns of Gene expression Can Be transmitted to Daughter Cells
As we have seen, once a cell in an organism differentiates into a particular cell type, it generally remains specialized in that way; if it divides, its daughters inherit the same specialized character. Perhaps the simplest way for a cell to remember transcription of Xist RNA Xist RNA spreads Xist RNA binds histone-modifying from one X chromosome “hand-over-hand” and continues to spread its identity is through a positive feedback loop in which a key transcription regulator activates, either directly or indirectly, the transcription of its own gene (see Figure 7–39). Interlocking positive feedback loops of the type shown in Figure 7–37 provide greater stability by buffering the circuit against fluctuations in the level of any one transcription regulator. Because transcription regulators are synthesized in the cytosol and diffuse throughout the nucleus, feedback loops based on this mechanism will affect both copies of a gene in a diploid cell. However, as discussed in this section, the expression pattern of a gene on one chromosome can differ from the copy of the same gene on the other chromosome (as in X-chromosome inactivation or in imprinting), and such differences can also be inherited through many cell divisions.
The ability of a daughter cell to retain a memory of the gene expression patterns that were present in the parent cell is an example of epigenetic inheritance: a heritable alteration in a cell or organism’s phenotype that does not result from changes in the nucleotide sequence of DNA (discussed in Chapter 4). (Unfortunately, the term epigenetic is sometimes also used to refer to all covalent modifications to histones and DNA, whether or not they are self-propagating; many of these modifications are erased each time a cell divides and do not generate cell memory.)
In Figure 7–53, we contrast two self-propagating epigenetic mechanisms that work in cis, affecting only one chromosomal copy with two self-propagating mechanisms that work in trans, affecting both chromosomal copies of a gene. Cells can combine these mechanisms to ensure that patterns of gene expression are maintained and inherited accurately and reliably—over a period of up to a hundred years or more, in our own case.