The Electric Genome: A Mechanistic Hypothesis for Nuclear Architecture and Gene Expression Bias

Genome organization is reproducible and linked to gene expression, but the forces shaping it remain poorly understood. This hypothesis proposes that chromatin positioning is directed by a weak radial electric field generated by the nuclear membrane potential. Although classical models predict rapid charge screening, the confined and viscous nuclear interior, regulated by ion pumps, limits this process and allows a residual field to persist. This field biases the movement of charged macromolecules within the gel-like nucleoplasm, similar to electrophoresis. DNA is uniformly negative, but chromatin charge varies. GC-rich regions bind more nucleosomes and are less negative, drawing them inward with positively charged nuclear speckles, hubs of gene expression. Epigenetic modifications further modulate chromatin charge, producing a self-organized, dynamic radial architecture that regulates transcription. This framework connects the noncoding genome to expression and helps explain variable disease penetrance. Its testable predictions open new avenues for deciphering the logic of genome regulation.