Abstract
The three-dimensional organization of the genome in mammalian interphase nuclei is intrinsically linked to the regulation of gene expression. Whole chromosome territories and their encoded gene loci occupy preferential positions within the nucleus that changes according to the expression profile of a given cell lineage or stage. To further illuminate the relationship between chromosome organization, epigenetic environment, and gene expression, here we examine the functional organization of chromosome X and corresponding X-linked genes in a variety of healthy human and disease state X diploid (XX) cells. We observe high frequencies of homologous chromosome X colocalization (or coalescence), typically associated with initiation of X-chromosome inactivation, occurring in XX cells outside of early embryogenesis. Moreover, during chromosome X coalescence significant changes in Xist, H3K27me3, and X-linked gene expression occur, suggesting the potential exchange of gene regulatory information between the active and inactive X chromosomes. We also observe significant differences in chromosome X coalescence in disease-implicated lymphocytes isolated from systemic lupus erythematosus (SLE) patients compared to healthy controls. These results demonstrate that X chromosomes can functionally interact outside of embryogenesis when X inactivation is initiated and suggest a potential gene regulatory mechanism aberration underlying the increased frequency of autoimmunity in XX individuals.
Highlights
The three-dimensional organization of the genome in mammalian interphase nuclei is intrinsically linked to the regulation of gene expression
We analyzed the differentiation of human embryonic stem cells (WA-09 cell line) toward the same neuronal progenitor cell (NPC) fate and unexpectedly identified high levels of X coalescence up to 10-days post induction (Fig. 1a,b)
Chromosome X coalescence gradually and significantly increased over the differentiation time course with a pronounced degree of association in NPCs (Fig. 1a,b). These results demonstrate that the association of X chromosomes can occur outside of embryogenesis with levels of coalescence varying among cell lineages
Summary
The three-dimensional organization of the genome in mammalian interphase nuclei is intrinsically linked to the regulation of gene expression. During chromosome X coalescence significant changes in Xist, H3K27me[3], and X-linked gene expression occur, suggesting the potential exchange of gene regulatory information between the active and inactive X chromosomes. We observe significant differences in chromosome X coalescence in disease-implicated lymphocytes isolated from systemic lupus erythematosus (SLE) patients compared to healthy controls These results demonstrate that X chromosomes can functionally interact outside of embryogenesis when X inactivation is initiated and suggest a potential gene regulatory mechanism aberration underlying the increased frequency of autoimmunity in XX individuals. During XCI the two X chromosomes colocalize (or coalesce) in the nuclear periphery of the interphase nucleus, utilizing trans-regulatory mechanisms to ensure only one X chromosome is selected for silencing while the other remains active[12,13]. This predisposition is further supported by the increased incidence of SLE in males with Klinefelter’s syndrome (47, XXY), in which SLE prevalence is equivalent to normal females (46, XX)[41], as well as lowered risk of SLE in women with Turner syndrome (45, X)[42]
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