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Pseudoautosomal region 1 overdosage affects the global transcriptome in iPSCs from patients with Klinefelter syndrome and high-grade X chromosome aneuploidies

ABSTRACT: Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by one or more supernumerary X chromosomes. Here, using a paradigmatic cohort of KS-inducible pluripotent stem cells (iPSCs) carrying 49-XXXXY, 48-XXXY, and 47-XXY karyotypes, we identified genes within the pseudoautosomal region 1 (PAR1) region as the most susceptible to dosage-dependent transcriptional dysregulation and therefore potentially responsible for the progressively worsening phenotype in higher grade X aneuploidies. By contrast, biallelically expressed non-PAR escape genes displayed high interclonal and interpatient variability in iPSCs and differentiated derivatives, suggesting that these genes could be associated with variable KS traits. By interrogating KS-iPSCs at single-cell resolution, we showed that PAR1 and non-PAR escape genes were not only resilient to X-inactive specific transcript (XIST)-mediated inactivation but also that their transcriptional regulation was disjointed from the absolute XIST expression level. Finally, we explored the transcriptional effects of X chromosome overdosage on autosomes and identified the transcription factor nuclear respiratory factor 1 as the master regulator of zinc finger protein X-linked. Our findings provided the first evidence of an X-dosage-sensitive autosomal transcription factor regulating an X-linked gene in low- and high-grade X aneuploidies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152001 | GEO | 2022/02/03

REPOSITORIES: GEO

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Project description:Background: In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. To date there has not been a comprehensive and directly comparative analysis of TS vs. KS regarding the changes on the molecular level Methods: We analyzed gene expression patterns with RNA-Seq and DNA methylation patterns with the CpGiant assay in lymphocytes, and chromatin conformation with in situ Hi-C in lymphoblastoid cell lines, from TS and KS patients together with their same gender controls. Results: In TS, differentially expressed escape genes were downregulated but differentially expressed inactive genes were upregulated. In KS, differentially expressed escape genes were upregulated while inactive genes appeared unchanged. Interestingly, 81 differentially expressed genes (DEGs) were associated with both TS and KS, and uniformly displayed expression changes into opposite directions. DEGs on the X chromosome and the autosomes were coexpressed in both TS and KS, indicating that there are molecular ripple effects of the changes in X chromosome dosage that extend to autosomes. Four potentially candidate genes (RPS4X, SEPT6, NKRF and CX0rf57) for KS were identified on Xq. Broad hypomethylation of the X chromosome is observed in TS whereas hypermethylation of chromosome X is present in KS. Only promoters of inactive genes were differentially methylated in both TS and KS while escape genes remained unchanged. The intrachromosomal contact map of the X chromosome in TS was partitioned into two superdomains and exhibited the structure of an active X chromosome. Conclusions: Components of the molecular basis of TS and KS were identified on the levels of the transcriptome and the epigenome, with candidate central genes on Xp for TS and on Xq for KS. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that are transmitting the gene dosage changes to the transcriptome.

Project description:Background: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Many types of senescing cells upregulate the THBD-PAR-1 signaling axis to remain viable. Vorapaxar, an FDA-approved PAR-1 inhibitor, blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. Methods: We evaluated the THBD-PAR1 pathway in liver biopsies from NAFLD patient cohorts with a spectrum of liver fibrosis. Chow fed mice were treated with viral vectors to over-express p16 specifically in hepatocytes and induce replicative senescence. Effects on the THBD-PAR-1 axis and regenerative capacity were assessed; the transcriptome of p16 over-expressing hepatocytes was characterized and we examined how conditioned medium from senescent but viable (dubbed ‘undead’) hepatocytes reprograms hepatic stellate cells. A genetically obese mouse model of NASH with little liver fibrosis, and a diet-induced mouse model of NASH with advanced fibrosis were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Results: Inducing senescence up-regulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR-1 signaling with vorapaxar interrupts this process, reduces the burden of ‘undead’ senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress Conclusion: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.

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Pseudoautosomal region 1 overdosage affects the global transcriptome in iPSCs from patients with Klinefelter syndrome and high-grade X chromosome aneuploidies

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