Premature ovarian insufficiency is associated with global alterations in the regulatory landscape and gene expression in balanced X-autosome translocations

Abstract

Background Patients with balanced X-autosome translocations and premature ovarian insufficiency (POI) constitute an interesting paradigm to study the effect of chromosome repositioning. Their breakpoints are clustered within cytobands Xq13–Xq21, 80% of them in Xq21, and usually, no gene disruption can be associated with POI phenotype. As deletions within Xq21 do not cause POI, and since different breakpoints and translocations with different autosomes lead to this same gonadal phenotype, a “position effect” is hypothesized as a possible mechanism underlying POI pathogenesis. Objective and methods To study the effect of the balanced X-autosome translocations that result in POI, we fine-mapped the breakpoints in six patients with POI and balanced X-autosome translocations and addressed gene expression and chromatin accessibility changes in four of them. Results We observed differential expression in 85 coding genes, associated with protein regulation, multicellular regulation, integrin signaling, and immune response pathways, and 120 differential peaks for the three interrogated histone marks, most of which were mapped in high-activity chromatin state regions. The integrative analysis between transcriptome and chromatin data pointed to 12 peaks mapped less than 2 Mb from 11 differentially expressed genes in genomic regions not related to the patients’ chromosomal rearrangement, suggesting that translocations have broad effects on the chromatin structure. Conclusion Since a wide impact on gene regulation was observed in patients, our results observed in this study support the hypothesis of position effect as a pathogenic mechanism for premature ovarian insufficiency associated with X-autosome translocations. This work emphasizes the relevance of chromatin changes in structural variation, since it advances our knowledge of the impact of perturbations in the regulatory landscape within interphase nuclei, resulting in the position effect pathogenicity.

Characteristics and mechanisms of X chromosome translocation

“…To investigate the effects of balanced X-autosome translocation resulting in POI, Di Battista ne-mapped breakpoints in six patients with POI and balanced X-autosome translocation and addressed the gene expression and chromatin accessibility changes in four of them. The results observe that translocation has a broad effect on the chromatin structure, suggesting that this study supports the hypothesis of positional effects as a causal mechanism for premature ovarian insu ciency associated with X-autosome translocation [20].…”

Transcriptomic profile of premature ovarian insufficiency with RNA-sequencing

“…Noteworthy genes such as FSHR and BMP15 were implicated, highlighting their vital roles in maintaining normal ovarian function ( Simoni and Casarini, 2014 ). Additionally, Johnson et al's recent research explored the epigenetic regulation of POI-associated genes, revealing irregular DNA methylation patterns ( Di-Battista et al, 2023 ). This sheds light on potential epigenetic mechanisms contributing to POI’s progression.…”