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

Area of Science:

• Genetics
• Stem Cell Biology
• Metabolomics

Background:

• Down syndrome (DS) is caused by trisomy 21 (exCh21), leading to congenital diseases, but the direct molecular impacts remain unclear.
• Mosaic Down syndrome patient-derived induced pluripotent stem cells (hiPSCs) offer a model to study exCh21 effects in isogenic lines.
• Understanding exCh21's cellular consequences is crucial for developing targeted Down syndrome therapies.

Purpose of the Study:

• To investigate the direct cellular and molecular impacts of an extra copy of chromosome 21 (exCh21) in Down syndrome.
• To identify key metabolites affected by exCh21 and their roles in DS-related pathologies.
• To explore Calcitriol's potential as a therapeutic agent for DS-associated developmental issues.

Main Methods:

• Generation of isogenic hiPSC lines from a mosaic Down syndrome patient, with and without exCh21.
• Transcriptomic and epigenomic (chromatin accessibility) analyses to assess cellular changes.
• Metabolomic profiling to identify dysregulated metabolites and functional assays to test their effects.

Main Results:

• exCh21 disrupts cellular transcriptome, induces DNA damage, and alters chromatin accessibility.
• Biosynthesis of 5-oxo-ETE and Calcitriol is significantly affected by exCh21.
• 5-oxo-ETE exacerbates DNA damage, while Calcitriol protects against it and mitigates exCh21-induced cardiogenesis defects.

Conclusions:

• exCh21 profoundly impacts cellular metabolism, DNA integrity, and developmental processes in Down syndrome.
• Calcitriol shows therapeutic potential by counteracting exCh21-induced DNA damage and supporting cardiogenesis.
• This study provides insights into exCh21's metabolic effects and suggests Calcitriol as a promising therapeutic target for Down syndrome.