Irregular nuclear shapes characterized by blebs, lobules, micronuclei, or invaginations are hallmarks of many cancers and human pathologies. Despite the correlation between abnormal nuclear shape and human pathologies, the mechanism by which the cancer nucleus becomes misshapen is not fully understood. Motivated by recent evidence that modifying chromatin condensation can change nuclear morphology, we conducted a high-throughput RNAi screen to identify epigenetic regulators that are required to maintain normal nuclear shape in human breast epithelial MCF-10A cells. We silenced 608 genes in parallel using an epigenetics siRNA library and used an unbiased Fourier analysis approach to quantify nuclear contour irregularity from fluorescent images captured on a high-content microscope. Using this quantitative approach, which we validated with confocal microscopy, we significantly expand the list of epigenetic regulators that impact nuclear morphology.