Abstract
X chromosome inactivation (XCI) is the transcriptional silencing of one X in female mammals, balancing expression of X genes between females (XX) and males (XY). In placental mammals non-coding XIST RNA triggers silencing of one X (Xi) and recruits a characteristic suite of epigenetic modifications, including the histone mark H3K27me3. In marsupials, where XIST is missing, H3K27me3 association seems to have different degrees of stability, depending on cell-types and species. However, the complete suite of histone marks associated with the Xi and their stability throughout cell cycle remain a mystery, as does the evolution of an ancient mammal XCI system. Our extensive immunofluorescence analysis (using antibodies against specific histone modifications) in nuclei of mammals distantly related to human and mouse, revealed a general absence from the mammalian Xi territory of transcription machinery and histone modifications associated with active chromatin. Specific repressive modifications associated with XCI in human and mouse were also observed in elephant (a distantly related placental mammal), as was accumulation of XIST RNA. However, in two marsupial species the Xi either lacked these modifications (H4K20me1), or they were restricted to specific windows of the cell cycle (H3K27me3, H3K9me2). Surprisingly, the marsupial Xi was stably enriched for modifications associated with constitutive heterochromatin in all eukaryotes (H4K20me3, H3K9me3). We propose that marsupial XCI is comparable to a system that evolved in the common therian (marsupial and placental) ancestor. Silent chromatin of the early inactive X was exapted from neighbouring constitutive heterochromatin and, in early placental evolution, was augmented by the rise of XIST and the stable recruitment of specific histone modifications now classically associated with XCI.
Highlights
In therian mammals, dosage compensation of X-linked genes in XX females and XY males is achieved by transcriptional silencing of X chromosome in females [1,2]
The inactive X chromosome of female basal placental mammals, like other placentals, harbours a stable accumulation of XIST RNA and H3K27me3, demonstrating that this system was established before the divergence of Afrotheria from other placental mammals 105 MYA [43]
In this study we examined the histone modification profiles of the inactive X chromosome in interphase cells of elephant, and two marsupial representatives that represent the therian mammals most distantly related to placental mammals
Summary
In therian (marsupial and placental) mammals, dosage compensation of X-linked genes in XX females and XY males is achieved by transcriptional silencing of X chromosome in females [1,2] (reviewed by [3]). Inactivation is established during early embryonic development [4,5], when the inactive X chromosome (Xi) acquires many chromatin changes that transform it into transcriptionally silent, facultative heterochromatin This process involves histone modifications and variants, DNA methylation, non-coding RNAs and differential nuclear compartmentalization (For reviews see [3,6,7]). Most studies of the molecular mechanism of X inactivation have been conducted on mice and humans, species representing a single clade of placental mammals (Euarchontoglires [8]) In these two species, initiation and propagation of inactivation is controlled in cis by a complex locus called the X inactivation centre. The role of these repressive marks is not fully understood, but they
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