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Inducible XIST-mediated trisomy 21 correction uncovers a USP16-p16 senescence axis driving epileptogenesis in Down syndrome

ABSTRACT: Down syndrome (DS), caused by human chromosome 21 (HSA21) trisomy, carries elevated epilepsy risk with unknown mechanisms. We integrated clinical epidemiology, fetal brain single-nucleus RNA sequencing, patient-derived induced pluripotent stem cell (iPSC) models, cerebral organoids, and in vivo chimeric mice to dissect this link. Clinical analysis of 1,365 DS individuals exhibited an age-stratified epilepsy prevalence pattern, with higher rates in older children. Fetal brain transcriptomes revealed neurogenesis defects, aging-related signatures, synaptic/metabolic dysregulation. We engineered an inducible XIST-mediated extra HSA21 silencing system in female DS iPSCs, showing HSA21 dosage correction reduced neural progenitor cell (NPC) senescence markers and neuronal hyperexcitability. Transcriptomic screening pinpointed USP16 as a key pro-aging candidate. Moreover, USP16 suppression and the senolytic combination dasatinib/quercetin reduced senescence-linked and hyperexcitability-associated readouts, supporting a USP16-p16-NPC aging axis as a therapeutic target for DS-associated epilepsy, with broader implications for aging-linked neurological disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE322851 | GEO | 2026/03/29

REPOSITORIES: GEO

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Inducible XIST-mediated trisomy 21 correction uncovers a USP16-p16 senescence axis driving epileptogenesis in Down syndrome [scRNA-Seq]

Project description:Down syndrome (DS), caused by human chromosome 21 (HSA21) trisomy, carries elevated epilepsy risk with unknown mechanisms. We integrated clinical epidemiology, fetal brain single-nucleus RNA sequencing, patient-derived induced pluripotent stem cell (iPSC) models, cerebral organoids, and in vivo chimeric mice to dissect this link. Clinical analysis of 1,365 DS individuals exhibited an age-stratified epilepsy prevalence pattern, with higher rates in older children. Fetal brain transcriptomes revealed neurogenesis defects, aging-related signatures, synaptic/metabolic dysregulation. We engineered an inducible XIST-mediated extra HSA21 silencing system in female DS iPSCs, showing HSA21 dosage correction reduced neural progenitor cell (NPC) senescence markers and neuronal hyperexcitability. Transcriptomic screening pinpointed USP16 as a key pro-aging candidate. Moreover, USP16 suppression and the senolytic combination dasatinib/quercetin reduced senescence-linked and hyperexcitability-associated readouts, supporting a USP16-p16-NPC aging axis as a therapeutic target for DS-associated epilepsy, with broader implications for aging-linked neurological disorders.

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Project description:Polycomb Repressive Complex 1 and histone H2A ubiquitination (ubH2A) contribute to embryonic stem cell (ESC) pluripotency by repressing lineage-specific gene expression. However, whether active deubiquitination co-regulates ubH2A levels in ESCs and during differentiation is not known. Here, we report that the histone H2A deubiquitinase Usp16 regulates H2A deubiquitination and gene expression in ESCs, and importantly, is required for ESC differentiation. Usp16 knockout is embryonic lethal in mice, but does not affect ESC viability or identity. Usp16 binds to the promoter regions of a large number of genes in ESCs and Usp16 binding is inversely correlated with ubH2A levels and positively correlated with gene expression levels. Intriguingly, Usp16-/- ESCs fail to differentiate due to ubH2A-mediated repression of lineage-specific genes. Finally, Usp16, but not the enzymatically inactive mutant, rescues the differentiation defects of Usp16-/- ESCs. Therefore, this study identifies Usp16 and H2A deubiquitination as critical regulators of ESC gene expression and differentiation. Examination of binding pattern of H2A deubiquitinase Usp16 and ubH2A in mouse embryonic stem cells and embroid bodies

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