16p11.2 microdeletion enhances gene expression variability between human IPSC-derived forebrain interneuron...

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• The 16p11.2 microdeletion is linked to neurodevelopmental disorders like autism and obesity.
• GABAergic forebrain interneuron development is implicated in 16p11.2 phenotypes.
• The genetic versus environmental contributions to clinical heterogeneity remain unclear.

Purpose of the Study:

• To investigate how the 16p11.2 microdeletion impacts the development of GABAergic forebrain interneuron progenitors.
• To identify molecular mechanisms underlying the neurodevelopmental and energy balance conditions associated with this microdeletion.

Main Methods:

• Utilized human-induced pluripotent stem cell (hiPSC)-derived ventral telencephalic interneuron progenitors in 2D culture.
• Compared isogenic hiPSCs with and without a heterozygous 16p11.2 microdeletion.
• Performed single-cell RNA sequencing and comparative bioinformatics analysis.

Main Results:

• Identified hundreds of differentially expressed transcripts in 16p11.2 heterozygous progenitors, associated with cell signaling and neurodevelopment.
• Observed significantly greater transcript-level variation in 16p11.2 heterozygous progenitors compared to wild-type controls.
• Found enrichment of cell cycle-related genes and genes linked to autism/obesity in highly variable regulons.

Conclusions:

• The 16p11.2 locus may play a role in stabilizing gene transcription across cells.
• Enhanced transcriptional variation in neural progenitors is a potential mechanism contributing to 16p11.2-associated neurodevelopmental phenotypes.
• This provides a molecular hypothesis for the heterogeneity observed in 16p11.2 syndrome.