X Chromosome Inactivation definition
Mammalian females are characterized by having two X chromosomes, unlike males having only one. Thus, if all genes on both X chromosomes were expressed and produce products, females would have twice as much protein as males have, which would have fatal consequences for females. However, this event is avoided by a mechanism known as dose compensation through a process called X chromosome inactivation or Lyon hypothesis (as suggested by the geneticist Mary Lyon in 1961).
X Chromosome Inactivation is based on the random inactivation of one X chromosomes present in the cell and occurs during early stages of development (in blastocyst stage). The choice made by cell (in mammals) of which X chromosome is inactivated appears to be random, causing cells to express the paternal X chromosome and others the maternal chromosome. However, once one of X chromosomes is inactivated in a cell, that information is hereditary and irreversible, and all of their offspring will have that chromosome inactive. In contrast, in marsupials the X chromosome inactive is always the paternal. In the case of existence more than two X chromosomes (aneuploidy), cell only maintains one chromosome active, inactivating all the chromosomes in excess.
Process of X Chromosome Inactivation is dependent on a genomic region called X-inactivation centre (XIC), where XIST (X-inactive specific transcript) gene is located. This gene is responsible for inactivation of chromosome from which is transcribed. Until the decision phase of chromosome inactivation, both X chromosomes express the XIST gene. However, when inactivation process begins, the chromosome that will remain active ceases expression of XIST gene and the chromosome to be inactivated increases its expression. This gene encodes a large non-coding RNA molecule that accumulates on the chromosome to be inactivated and coats it, preventing its transcription. On the other hand, the active chromosome expresses TSIX gene, called an antisense companion of XIST gene, because it is transcribed in the opposite direction along the entire XIST gene. This gene also expresses a large molecule of non-coding RNA that only acts on the chromosome from which it is transcribed, however its function is to keep the chromosome active. Thus, these two genes, XIST and TSIX, have antagonistic action, i.e., on a chromosome when expression of one increases, expression of the other decreases.
Inactivated chromosome is silenced through DNA methylation and histone deacetylation, which leads to its packaging in heterochromatin forming a structure called ‘Barr corpuscle’ (it is located at the nucleus periphery and it is possible to observe it during interphase of mitosis). However, this packaging of chromosome does not inhibit expression of all genes contained in chromosome, some genes continue to be expressed, such as genes located in various regions of short arm and in a region of long arm of chromosome.
