Box 1 Regulation of the X chromosome in eutherian mammals

X upregulation is the process by which the active X chromosome (Xa) is upregulated in both sexes to balance expression between the X and the autosomes. The molecular mechanisms of the process are unknown.

Random X inactivation is the process by which one X chromosome is silenced in female embryos in order to avoid X hyperexpression due to X upregulation and to balance gene dosage between the sexes. Random X inactivation silences either the paternal or maternal X chromosome at the blastocyst stage and persists into adulthood. The noncoding RNA transcribed from Xist is essential for the onset of silencing. Xist RNA coats the X chromosome in cis and recruits a protein complex to establish repressive epigenetic modifications and implement gene silencing. Escape from random X inactivation affects about 15% of human genes and 3% of mouse genes, most of these genes being protein coding.

Imprinted paternal X inactivation is the process by which the paternal X chromosome is silenced in early female embryos before implantation. This paternal X inactivation persists in extraembryonic tissues (as shown in mice, but not well studied in humans) but is reversed in the inner cell mass before random X inactivation. This silencing process is Xist dependent, although it is controversial whether Xist is necessary for initiation. Escape from imprinted paternal X inactivation has been observed for some genes (which may differ from those that escape random X inactivation), but no complete survey is available.

Meiotic sex-chromosome inactivation (MSCI) is the process of silencing of both the X and Y chromosomes in male meiosis and occurs in almost all organisms that have differentiated sex chromosomes, including humans. As in somatic X inactivation, Xist RNA coats the X chromosome during MSCI. However, Xist is not required for silencing. MSCI is associated with recruitment of DNA repair proteins such as the histone variant H2AX and MDC1 (mediator of DNA damage checkpoint 1). Escape from MSCI characterizes a set of miRNA genes such as mir-221, mir-374, mir-470 and mir-741, which may be important for spermatogenesis.