GAS41 controls nuclear morphology by targeting multiple genes encoding nuclear envelope proteins

Nuclear morphology is normally maintained in a defined manner within a given cell type, and aberrant nuclear morphology correlates with a wide range of human diseases. However, the underlying mechanisms that define nuclear morphology are largely unknown. Here we show that depletion of YEATS family protein-GAS41 exhibits striking nuclear shape abnormalities.The misshapen nuclei can be rescued by GAS41 wild type, but not by GAS41 Y74A W93A mutant deficient in histone H3 lysine 27 acetylation (H3K27ac) binding. GAS41 depletion significantly decreased the expression of multiple genes encoding nuclear envelope (NE) architecture components including LMNB1, LMNB2, SYNE4 and LEMD2, and dysregulation of these genes directly leads to nuclear shape abnormalities. Using mass spectrometry and ChIP sequencing, we found GAS41 interacts with BRD2 and mediator components MED14 /MED23, and co-localizes with H3K27ac and BRD2 at target gene loci. The occupancy of BRD2 and MED14/MED23 at LMNB1, LMNB2, SYNE4 and LEMD2 is dependent on the presence of GAS41. Depletion of GAS41 or disruption of GAS41-H3K27ac recognition abrogated GAS41 binding at these gene loci, which further prevents the enrichment of BRD2, mediator complex as well as RNA polymerase II, thus consequently deactivated target gene expression and leading to nuclear morphology abnormalities. Overall, our study identified GAS41 as a novel nuclear shape regulator that works in concert with BRD2/mediator complex to control nuclear morphology