X染色体の不活性化とは哺乳類のメスが持つ2つのX染色体のうちの1つが不活性化されるプロセスをいう。X染色体の不活性化は片方のX染色体が抑圧性のヘテロクロマチンにより取り囲まれることにより起こる。X染色体の不活性化はオスがX染色体を1つしか持たないのに対して、メスがX染色体を2つ持つことによりX染色体由来の遺伝子産物（X chromosome gene product）を2倍生じることがないように起こる。（遺伝子量補償参照）どちらのX染色体が不活性化されるかはネズミや人間のような高等哺乳類（higher mammals）においてはランダムであるが、いったん不活性化が起こるとその細胞においては変化しない。これに対してフクロネズミにおいては父親由来のX染色体が選択的に不活性化される。
Mary Lyon proposed the random inactivation of one female X chromosome in 1961年 to explain the mottled phenotype of female mice ヘテロ接合型 for coat color 遺伝子. The Lyon hypothesis also accounted for the findings that one copy of the X chromosome in female cells was highly condensed, and that mice with only one copy of the X chromosome developed as fertile females.
All mouse cells undergo an early, imprinted inactivation of the paternally-derived X chromosome in four-cell stage 胚. The extraembryonic tissue (which give rise to the 胎盤 and other tissues supporting the embryo) retain this early imprinted inactivation, and thus only the maternal X chromosome is active in these tissues.
In the early blastocyst, this initial, imprinted X-inactivation is reversed in the cells of the inner cell mass (which give rise to the embryo), and in these cells both X chromosomes become active again. Each of these cells then independently randomly inactivates one copy of the X chromosome. This inactivation event is irreversible during the lifetime of the cell, so all the descendants of a cell which inactivated a particular X chromosome will also inactivate that same chromosome. This leads to mosaicism if a female is ヘテロ接合型 for a X-linked gene, which can be observed in the coloration of 三毛猫.
Normal females possess two X chromosomes, and in any given cell one chromosome will be active (designated as Xa) and one will be inactive (Xi). However, studies of individuals with extra copies of the X chromosome show that in cells with more than two X chromosomes there is still only one Xa, and all the remaining X chromosomes are inactivated. This indicates that the default fate of the X chromosome in females is inactivation, but one X chromosome is always selected to remain active.
It is hypothesized that there is an autosomally-encoded 'blocking factor' which binds to the X chromosome and prevents its inactivation. The model postulates that there is limiting blocking factor, so once the available blocking factor molecule binds to one X chromosome the remaining X chromosome(s) are not protected from inactivation. This model is supported by the existence of a single Xa in cells with many X chromosomes and by the existence of two active X chromosomes in cell lines with twice the normal number of autosomes.
Sequences at the X inactivation center (XIC), present on the X chromosome, control the silencing of the X chromosome. The hypothetical blocking factor is predicted to bind to sequences within the XIC.
The X-inactivation center (XIC) on the X chromosome is necessary and sufficient to cause X-inactivation. Chromosomal translocations which place the XIC on an 常染色体 lead to inactivation of the autosome, and X chromosomes lacking the XIC are not inactivated.
The Xist gene encodes a large RNA which is not believed to encode a 蛋白質. The Xist RNA is the major effector of X-inactivation. The inactive X chromosome is coated by Xist RNA, whereas the Xa is not. The Xist gene is the only gene which is expressed from the Xi but not from the Xa. X chromosomes which lack the Xist gene cannot be inactivated. Artificially placing and expressing the Xist gene on another chromosome leads to silencing of that chromosome.
Prior to inactivation, both X chromosomes weakly express Xist RNA from the Xist gene. During the inactivation process, the future Xa ceases to express Xist, whereas the future Xi dramatically increases Xist RNA production. On the future Xi, the Xist RNA progressively coats the chromosome, spreading out from the XIC; the Xist RNA does not localize to the Xa. The silencing of genes along the Xi occurs soon after coating by Xist RNA.
Like Xist, the Tsix gene encodes a large RNA which is not believed to encode a protein. The Tsix RNA is transcribed antisense to Xist, meaning that the Tsix gene overlaps the Xist gene and is transcribed on the opposite strand of DNA from the Xist gene. Tsix is a negative regulator of Xist; X chromosomes lacking Tsix expression (and thus having high levels of Xist transcription) are inactivated much more frequently than normal chromosomes.
Like Xist, prior to inactivation, both X chromosomes weakly express Tsix RNA from the Tsix gene. Upon the onset of X-inactivation, the future Xi ceases to express Tsix RNA (and increases Xist expression), whereas Xa continues to express Tsix for several days.
The inactive X chromosome does not express the majority of its genes, unlike the active X chromosome. This is due to the silencing of the Xi by repressive ヘテロクロマチン, which coats the Xi DNA and prevents the expression of most genes.
Compared to the Xa, the Xi has high levels of DNA methylation, low levels of histone acetylation, low levels of histone H3 lysine-4 methylation, and high levels of histone H3 lysine-9 methylation, all of which are associated with gene silencing. Additionally, a histone variant called macroH2A is exclusively found on ヌクレオソームs along the Xi.
DNA packaged in heterochromatin, such as the Xi, is more condensed than DNA packaged in ユークロマチン, such as the Xa. The inactive X forms a discrete body within the nucleus called a バー小体. The Barr body is generally located on the periphery of the 細胞核, is late DNA複製 within the 細胞周期, and, as it contains the Xi, contains heterochromatin modifications and the Xist RNA.
A fraction of the genes along the X chromosome escape inactivation on the Xi. The Xist gene is expressed at high levels on the Xi and is not expressed on the Xa. Other genes are expressed equally from the Xa and Xi; mice contain few genes which escape silencing whereas up to a quarter of human X chromosome genes are expressed from the Xi. Many of these genes occur in clusters.
Many of the genes which escape inactivation are present along regions of the X chromosome which, unlike the majority of the X chromosome, contain genes also present on the Y染色体. These regions are termed pseudoautosomal regions, as individuals of either sex will receive two copies of every gene in these regions (like an 常染色体), unlike the majority of genes along the sex chromosomes. Since individuals of either sex will receive two copies of every gene in a pseudoautosomal region, no dosage compensation is needed for females, so it is postulated that these regions of DNA have evolved mechanisms to escape X-inactivation. The genes of pseudoautosomal regions of the Xi do not have the typical modifications of the Xi and have little Xist RNA bound.
The existence of genes along the inactive X which are not silenced explains the defects in humans with abnormal numbers of the X chromosome, such as ターナー症候群 (X0) or クラインフェルター症候群 (XXY). Theoretically, X-inactivation should eliminate the differences in gene dosage between affected individuals and individuals with a normal chromosome complement, but in affected individuals the dosage of these non-silenced genes will differ as they escape X-inactivation.