Genomic Environment Predicts Expression Patterns on the Human Inactive X Chromosome

Abstract

What genomic landmarks render most genes silent while leaving others expressed on the inactive X chromosome in mammalian females? To date, signals determining expression status of genes on the inactive X remain enigmatic despite the availability of complete genomic sequences. Long interspersed repeats (L1s), particularly abundant on the X, are hypothesized to spread the inactivation signal and are enriched in the vicinity of inactive genes. However, both L1s and inactive genes are also more prevalent in ancient evolutionary strata. Did L1s accumulate there because of their role in inactivation or simply because they spent more time on the rarely recombining X? Here we utilize an experimentally derived inactivation profile of the entire human X chromosome to uncover sequences important for its inactivation, and to predict expression status of individual genes. Focusing on Xp22, where both inactive and active genes reside within evolutionarily young strata, we compare neighborhoods of genes with different inactivation states to identify enriched oligomers. Occurrences of such oligomers are then used as features to train a linear discriminant analysis classifier. Remarkably, expression status is correctly predicted for 84% and 91% of active and inactive genes, respectively, on the entire X, suggesting that oligomers enriched in Xp22 capture most of the genomic signal determining inactivation. To our surprise, the majority of oligomers associated with inactivated genes fall within L1 elements, even though L1 frequency in Xp22 is low. Moreover, these oligomers are enriched in parts of L1 sequences that are usually underrepresented in the genome. Thus, our results strongly support the role of L1s in X inactivation, yet indicate that a chromatin microenvironment composed of multiple genomic sequence elements determines expression status of X chromosome genes.

Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus

“…LINE-1 repeats fit such predictions, particularly on the human X (8)(9)(10). Distinct distributions of other repeats classify some mouse X genes (5).…”

“…Nevertheless, even large inserts can be susceptible to integration site effects (24). In this study we extend the use of BAC transgenes to evaluate escape genes, because inactive X expression patterns are likely influenced by genomic sequence environment (3,(9)(10)(11). We established that transgenic Jarid1c escapes XCI at all 4 sites tested, whereas other transgene transcripts were appropriately X-inactivated.…”

“…X-inactivated and escape domains differ in sequence composition, particularly repetitive element distribution (3,5,(8)(9)(10)(11).…”

X chromosome inactivation: A silence that needs to be broken

“…Consistent with this hypothesis, studies on the localization of genes within the Xi chromosome territory showed that a gene silencing compartment was formed by intergenic DNA sequences, and X-linked genes were moved into this compartment when being silenced (Chaumeil et al, 2006). The distribution profiles of LINE-1 were shown to be consistent with the distribution of Xist-mediated gene silencing (Bailey et al, 2000;Carrel et al, 2006;Chow et al, 2010;Tang et al, 2010). In RNA FISH, large LINE-1 RNA foci (LINE-1 RNA cloud) were detected in differentiating ES cells (Chow et al, 2010).…”

Triagem funcional de genes envolvidos no processo de manutenção da inativação do cromossomo X em humanos

“…Em humanos (mas não em camundongos) foi observado que o número de sequencias LINE-1 no cromossomo X é maior do que nos autossomos. Genes destinados a inativação contém grande número de repetições LINE-1 enquanto que a densidade dessas repetições em genes que escapam a inativação é bem mais baixa (Lyon, 1998;Bailey et al, 2000;Ross et al, 2005;Carrel et al, 2006). Em camundongos, um outro tipo de repetição, as LTRs (long terminal repeats) parece ocorrer com menos frequência em genes que escapam à XCI (Tsuchiya et al, 2004).…”