Dosage Compensation in Mammals

Abstract

SUMMARYMany organisms show major chromosomal differences between sexes. In mammals, females have two copies of a large, gene-rich chromosome, the X, whereas males have one X and a small, gene-poor Y. The imbalance in expression of several hundred genes is lethal if not dealt with by dosage compensation. The male-female difference is addressed by silencing of genes on one female X early in development. However, both males and females now have only one active X chromosome. This is compensated by twofold up-regulation of genes on the active X. This complex system continues to provide important insights into mechanisms of epigenetic regulation.

RNAi and Heterochromatin Assembly

“…Nonetheless, antisense RNA has been implicated in the most widely studied epigenetic phenomena of all, imprinting and X inactivation (see Barlow andBartolomei 2014 andBrockdorff andTurner 2014, respectively). In the case of X inactivation, a 17-kb spliced and polyadenylated noncoding RNA known as Xist is required to silence the inactive X chromosome from which it is expressed.…”

Dosage Compensation inDrosophila

“…One can envisage two very general models for regulating a whole chromosome. A single site or a very limited number of sites might control the chromosome in cis, as is the case in mammalian X inactivation via the region called the X inactivation center (see Brockdorff and Turner 2014). This mechanism requires either compartmentalization of the complex to a specific place in the nucleus or regulation over very long distances through the spreading of factors from the central control region to the rest of the chromosome.…”

“…We now know that in organisms belonging to distantly related groups-from round worms to mammals-transcriptional regulation leading to equal products of X-linked genes in males and females has been achieved in different ways: by decreasing the level of transcription of the two doses of X-linked genes in hermaphrodites relative to males (Caenorhabditis elegans) or by hypertranscribing the X chromosome in both males and females and then shutting down one of the two X chromosomes throughout most of its length in the somatic cells of females (mammals). The mechanisms underlying dosage compensation in these forms are described in Strome et al (2014) and Brockdorff and Turner (2014).…”

“…One of the most intriguing and mysterious aspects of dosage compensation in both mammals and Drosophila is the role of ncRNAs in targeting compensation to the correct chromosome (reviewed in ; also see Brockdorff and Turner 2014). Two ncRNAs, called RNA on X (roX), are dissimilar in size and sequence, and yet function redundantly to target the MSL complex to the male X chromosome in Drosophila (Meller and Rattner 2002).…”

Germline and Pluripotent Stem Cells

“…In female mouse embryos (XX), the paternally inherited X chromosome is always inactivated during the cleavage stages and remains so in the extraembryonic tissues (i.e., the TE and the placenta; Lee 2003, Okamoto et al 2005). But, in the ICM, the inactive X is reactivated and this is followed by random inactivation of one X chromosome after differentiation in the ICM-derived lineages (Mak et al 2004; for more detail, see Figs 4 and 6 of Brockdorff and Turner 2014). Mechanistically, imprinted X inactivation (i.e., paternal X inactivation) in the preimplantation embryo involves expression of the noncoding RNA Xist from the paternal X chromosome, whose "coating" of the chromosome is thought to lead to gene silencing and the establishment of repressive epigenetic modifications (Heard 2004).…”