Changes in 3D Chromatin Organization Drive Topologically Determined Gene Expression in the Poststroke Mouse Cortex

Area of Science:

• Genomics
• Neuroscience
• Epigenetics

Background:

• High-throughput transcriptomics show gene expression changes in cerebral ischemia.
• 3D chromatin architecture and looping alterations driving these changes are unexplored.
• This study investigates dynamic changes in topologically associating domains and chromatin loops in the ischemic cortex.

Purpose of the Study:

• To map genome-wide 3D chromatin architecture changes in the ischemic cerebral cortex.
• To identify stroke-induced alterations in topologically associating domains and chromatin loops.
• To evaluate the contribution of these architectural changes to post-stroke transcriptional alterations.

Main Methods:

• High-throughput chromatin conformation capture (Hi-C) was used to profile 3D chromatin architecture.
• RNA sequencing identified differentially expressed genes associated with stroke.
• Experiments were conducted on adult mice following middle cerebral artery occlusion and reperfusion.

Main Results:

• 293 altered topologically associating domains and 4323 differentially altered chromatin loops were identified post-stroke.
• Altered loops linked novel enhancer and silencer elements to 88 upregulated and 96 downregulated genes.
• Upregulated genes involved endothelial and immune functions; downregulated genes related to neuronal and synaptic functions.

Conclusions:

• This is the first study to map 3D chromatin changes in the adult cerebral cortex after ischemic stroke.
• Novel regulatory elements associated with stroke-altered genes were discovered.
• Dynamic chromatin remodeling and looping fine-tune gene expression post-stroke, impacting cellular functions.