Single-cell multiplex chromatin and RNA interactions in ageing human brain

Area of Science:

• Genomics
• Molecular Biology
• Neuroscience

Background:

• Chromatin complexes are dynamic and heterogeneous, changing with cell differentiation and age.
• Understanding chromatin organization and its relation to gene expression in single cells is crucial.

Purpose of the Study:

• To develop a novel technique for simultaneous profiling of chromatin interactions, gene expression, and RNA-chromatin associations in single cells.
• To investigate cellular heterogeneity and chromatin organization in the aging human frontal cortex.

Main Methods:

• Introduced the multinucleic acid interaction mapping in single cells (MUSIC) technique.
• Applied MUSIC to human frontal cortex samples from older donors.
• Analyzed multiplex chromatin interactions, gene expression, and RNA-chromatin associations at the single-nucleus level.

Main Results:

• MUSIC delineated diverse cortical cell types and states.
• Fewer short-range chromatin interactions correlated with 'older' transcriptomic signatures and Alzheimer's disease pathology.
• Observed cell-type-specific chromatin contacts between cis-regulatory elements and promoters, impacting gene expression.
• Identified highly heterogeneous XIST RNA-X chromosome interactions and diverse X chromosome organizations in female cortical cells.

Conclusions:

• MUSIC is a powerful tool for exploring chromatin architecture and transcription at cellular resolution in complex tissues.
• The study provides insights into chromatin dynamics, aging, and Alzheimer's disease pathology at the single-cell level.
• Revealed sex-specific differences in X chromosome organization and regulation.