Dosage compensation in mammals: fine-tuning the expression of the X chromosome

Abstract

Mammalian females have two X chromosomes and males have only one. This has led to the evolution of special mechanisms of dosage compensation. The inactivation of one X chromosome in females equalizes gene expression between the sexes. This process of X-chromosome inactivation (XCI) is a remarkable example of longrange, monoallelic gene silencing and facultative heterochromatin formation, and the questions surrounding it have fascinated biologists for decades. How does the inactivation of more than a thousand genes on one X chromosome take place while the other X chromosome, present in the same nucleus, remains genetically active? What are the underlying mechanisms that trigger the initial differential treatment of the two X chromosomes? How is this differential treatment maintained once it has been established, and how are some genes able to escape the process? Does the mechanism of X inactivation vary between species and even between lineages? In this review, X inactivation is considered in evolutionary terms, and we discuss recent insights into the epigenetic changes and developmental timing of this process. We also review the discovery and possible implications of a second form of dosage compensation in mammals that deals with the unique, potentially haploinsufficient, status of the X chromosome with respect to autosomal gene expression.In mammals, dosage compensation for X-linked gene products between XX and XY individuals is achieved by silencing one of the two X chromosomes in female cells (Lyon 1961). A second form of dosage compensation maintains a balanced expression between X-linked and autosomal genes by doubling the transcriptional output of the active X. These distinctive regulatory processes derive from the unique evolution of the sex chromosomes. In eutherians, X-chromosome inactivation (XCI) affects the paternal or maternal X chromosome randomly during early development, and the inactive state is then stably inherited, giving rise to adults that are mosaics for two cell types, expressing one or the other X chromosome. The initiation of X inactivation is controlled by the X-inactivation center (Xic), which produces the noncoding Xist transcript responsible for triggering silencing in cis. In marsupials and in the extraembryonic tissues of some placental mammals such as rodents, XCI is imprinted, with the paternal X chromosome (Xp) being inactivated. Imprinted XCI has been proposed to represent the ancestral form of X inactivation. Furthermore, it has been proposed that imprinted XCI may have arisen as a carryover effect from meiotic sex chromosome inactivation (MSCI) in the male germline, a process found in several species that results in silencing of the X and Y chromosomes. We discuss data suggesting that in mice, MSCI may not be essential for imprinted Xp inactivation, raising the possibility that imprinted XCI may have arisen more than once during evolution. We also discuss new insights into the phenomenon of escape from XCI. Although XCI affects most of the X chromosome, several X-linked gene...

Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

“…Male recipient cells were used to construct the radiation hybrid panel, so some clones had both a hamster and a mouse X-chromosome inactivation center 35 . However, the autoregulation represented by decreased cis ceQTL effect size cannot be a result of Xchromosome inactivation.…”

Genomic DNA methylation analyses reveal the distinct profiles in castor bean seeds with persistent endosperms

“…DNA methylation has shown broad-ranging functions, including the regulation of gene expression, involvement in chromatin organization, and protection of the genome from invading and mobile DNA elements (Heard and Disteche, 2006;Klose and Bird, 2006;Feinberg, 2007). Usually, DNA methylation can be maintained through mitotic cell division; thus, it is a relatively stable and heritable epigenetic marker (Henderson and Jacobsen, 2007).…”

Inactivation du chromosome X et pluripotence

“…Lié au chromosome X, le gène Xist produit un ARN non codant de grande taille possédant la propriété unique > L'inactivation d'un chromosome X (ICX) chez les femelles (XX) est le processus qui permet de compenser le niveau d'expression des gènes du chromosome X entre les mammifères mâles (XY) et femelles (XX) [1]. Chez la souris, il existe deux formes distinctes d'ICX : la première caractérise les cellules de l'embryon préimplantatoire et des annexes extraembryonnaires, et affecte exclusivement le chromosome X d'origine paternel (Xp) ; en revanche, dans les cellules de l'embryon postimplantatoire ainsi que dans les cellules adultes, le deuxième processus d'inactivation peut cibler aussi bien le chromosome X d'origine paternelle (Xp) que d'origine maternelle (Xm).…”

“…L'inactivation aléatoire se met en place lorsque ces cellules engagent leur processus de différenciation pour former les trois lignages primordiaux de l'embryon (ectoderme, endoderme, mésoderme). Par la suite, toutes les cellules issues des premières cellules ayant inactivé soit le Xp soit le Xm conservent ce profil d'inactivation, générant ainsi des individus femelles mosaïques composés de clones cellulaires ayant inactivé soit l'un soit l'autre des deux de recouvrir le chromosome X qui le produit pour enclencher le processus de répression [1]. Dans les cellules pluripotentes femelles de l'embryon, issues de la MCI et de la lignée germinale, ainsi que dans les cellules ES, l'expression de Xist est réprimée à partir des deux chromosomes X actifs.…”