Repeat expansions in C9orf72 rewire the 3D chromatin landscape in ALS

Abstract Amyotrophic lateral sclerosis (ALS) is frequently driven by GGGGCC short tandem repeat (STR) expansions in C9orf72 , yet the mechanisms by which these expansions lead to neurodegeneration remain incompletely understood. Here, we propose a novel mechanism involving higher-order chromatin architecture where C9orf72 -STR expansions induce widespread, neuron-specific gains in chromatin loops that are closely linked to transcriptomic dysregulation in ALS. These ectopic loops colocalize with the genomic binding sites of C9orf72 -STR RNAs and the architectural protein CTCF, supporting a model in which RNA-DNA interactions promote aberrant loop formation. Together, our findings demonstrate how C9orf72 -STR expansions remodel the neuronal genome and disrupt gene expression, uncovering an RNA-driven mechanism of chromatin reorganization in C9-ALS that connects altered nuclear topology to gene dysregulation in neurodegeneration.