Mechanistic concepts in X inactivation underlying dosage compensation in mammals

Abstract

Mammals inactivate one of the two female X chromosomes to compensate for the unequal copy number of X-linked genes between males and females. This process of X inactivation entails the silencing of one X chromosome in a developmentally regulated manner. In this work, we review recent findings in X inactivation and discuss how these advance the mechanistic understanding. Recent results provide an insight how the cell counts and chooses the appropriate number of X chromosomes to inactivate, how chromosome-wide gene repression is coordinated and how a stable inactive X chromosome is established. Key components of this complex regulatory system have now been identified and provide entry points for understanding epigenetic regulation in mammals. A majority of the data has been obtained from studying mice. It is presently not clear how general these findings can be applied to other mammalian species. We try to assess this aspect from data, which has become available.

Sex Modifies Genetic Effects on Residual Variance in Urinary Calcium Excretion in Rat (Rattus norvegicus)

“…0.1). Various X-chromosomal peculiarities, including pseudoautosomal recombination and mutation (Lien et al 2000;Lercher and Hurst 2002;Filatov and Gerrard 2003;Ross et al 2005), variable X-chromosomal deactivation (Heard and Disteche 2006;Leeb and Wutz 2010) including among lineages (Patrat et al 2009) might explain such effects (Charlesworth et al 1987;Evans et al 2007). Some molecular chaperones including hsp70, hsp90, and Piwi-interacting RNA canalize variability in morphological and over environmental and genetic axes (Gibert et al 2007;Fernandino et al 2011;Gangaraju et al 2011).…”

Caenorhabditis elegans Dosage Compensation Regulates Histone H4 Chromatin State on X Chromosomes

“…The active X (Xa) and Xi chromosomes can be distinguished by unique sets of activating and repressive epigenetic marks, respectively. The Xi chromosome is depleted of H3K4me2/3 and acetylation of H3K9, H4K5, K8, K12 and K16, H3R17me2, and H3R26me but is enriched for H3K9me2/3, H3K27me3, H4R3me2, H4K20me1, H2AK119ub1, and macro-H2A relative to the active X chromosome and autosomes (27,41,58). To achieve upregulation of the X chromosome in flies, the male-specific lethal (MSL) complex loads across the single X chromosome in males, dependent on msl-2 expression (36).…”

“…X chromosome upregulation is thought to occur in both sexes in mammals and worms (14,24,53), resulting in the need to prevent X-linked hyperexpression in females and hermaphrodites. To achieve that, in mammals, XX females inactivate one of the two X chromosomes (27,41,58), while in the worm Caenorhabditis elegans, XX hermaphrodites downregulate both X chromosomes 2-fold (11,50). Dosage compensation mechanisms in mammals and flies involve changes in chromatin.…”

“…Dosage compensation mechanisms in mammals and flies involve changes in chromatin. Mammalian X chromosome inactivation is initiated by the Xist noncoding RNA and is accomplished by spreading facultative heterochromatin over the entire inactive X (Xi) chromosome (27,41,58). The active X (Xa) and Xi chromosomes can be distinguished by unique sets of activating and repressive epigenetic marks, respectively.…”

Non-Coding RNAs: A Dynamic and Complex Network of Gene Regulation

“…Regulation involves sequences around the Xist gene, which makes up the complex genetic locus of the XIC. Xist RNA has been identified in human and mouse and apparently conserved among placental mammals [135].…”