# Trisomy 21-driven metabolite alterations are linked to cellular injuries in Down syndrome

## TL;DR

This study identifies how an extra copy of chromosome 21 in Down syndrome disrupts metabolism and causes cellular damage, offering potential therapeutic targets.

## Contribution

The study reveals specific metabolite alterations and their effects on DNA damage and cardiogenesis in Down syndrome.

## Key findings

- ExCh21 disrupts metabolic processes and causes DNA damage and chromatin accessibility changes.
- 5-oxo-ETE promotes DNA damage, while Calcitriol protects against it and supports cardiogenesis.
- Calcitriol activates the VDR receptor, enhancing gene transcription and potentially mitigating Down syndrome effects.

## Abstract

Down syndrome (DS) arises from a genetic anomaly characterized by an extra copy of chromosome 21 (exCh21). Despite high incidence of congenital diseases among DS patients, direct impacts of exCh21 remain elusive. Here, we established a robust DS model harnessing human-induced pluripotent stem cells (hiPSCs) from mosaic DS patient. These hiPSC lines encompassed both those with standard karyotype and those carrying an extra copy of exCh21, allowing to generate isogenic cell lines with a consistent genetic background. We unraveled that exCh21 inflicted disruption upon the cellular transcriptome, ushering in alterations in metabolic processes and triggering DNA damage. The impact of exCh21 was also manifested in profound modifications in chromatin accessibility patterns. Moreover, we identified two signature metabolites, 5-oxo-ETE and Calcitriol, whose biosynthesis is affected by exCh21. Notably, supplementation with 5-oxo-ETE promoted DNA damage, in stark contrast to the protective effect elicited by Calcitriol against such damage. We also found that exCh21 disrupted cardiogenesis, and that this impairment could be mitigated through supplementation with Calcitriol. Specifically, the deleterious effects of 5-oxo-ETE unfolded in the form of DNA damage induction and the repression of cardiogenesis. On the other hand, Calcitriol emerged as a potent activator of its nuclear receptor VDR, fostering amplified binding to chromatin and subsequent facilitation of gene transcription. Our findings provide a comprehensive understanding of exCh21’s metabolic implications within the context of Down syndrome, offering potential avenues for therapeutic interventions for Down syndrome treatment.

The online version contains supplementary material available at 10.1007/s00018-024-05127-0.