Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, 04023-900, Brazil.
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Epigenetics Chromatin. 2023 May 19;16(1):19. doi: 10.1186/s13072-023-00493-8.
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.
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.
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.
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.
携带平衡 X-常染色体易位和卵巢早衰（POI）的患者构成了研究染色体重定位影响的有趣范例。他们的断点聚集在 Xq13-Xq21 带内，其中 80%位于 Xq21 上，通常与 POI 表型无关的基因缺失不能与之相关联。由于 Xq21 内的缺失不会导致 POI，并且由于不同的断点和与不同常染色体的易位导致相同的性腺表型，因此假设“位置效应”是 POI 发病机制的一种可能机制。
为了研究导致 POI 的平衡 X-常染色体易位的影响，我们对六名携带 POI 和平衡 X-常染色体易位的患者进行了精细定位断点，并对其中的四名患者进行了基因表达和染色质可及性变化的研究。
我们观察到 85 个编码基因的差异表达，与蛋白质调节、多细胞调节、整合素信号和免疫反应途径相关，以及三个被询问的组蛋白标记的 120 个差异峰，其中大多数被映射到高活性染色质状态区域。转录组和染色质数据的综合分析指出，在与患者染色体重排无关的基因组区域中，有 11 个差异表达基因的少于 2Mb 处有 12 个映射峰，这表明易位对染色质结构有广泛的影响。
由于在患者中观察到对基因调控的广泛影响，我们在这项研究中观察到的结果支持位置效应作为与 X-常染色体易位相关的卵巢早衰的致病机制假说。这项工作强调了染色质变化在结构变异中的相关性，因为它提高了我们对调节景观中干扰在有丝分裂核内导致位置效应致病性的影响的认识。
