Chromatin tethering to the nuclear envelope enhances its accessibility to RNAPII and promotes chromatin asymmetric organization

Abstract The intrinsic tendency of chromatin to self-attract competes with its association with RNA Polymerase II (RNAPII), a prerequisite for efficient transcription. Using high-resolution live imaging of chromatin and RNAPII organization in Drosophila larval muscle nuclei, we demonstrate that chromatin tethering to the nuclear envelope via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is essential for maintaining chromatin three-dimensional organization. Disruption of chromatin-lamina interactions either in LINC mutants or following knockdown of Barrier-to-Autointegration Factor (BAF) results in enhanced chromatin clustering in the nucleoplasm and reduced RNAPII-chromatin interaction. Consistent with these observations, computer simulations revealed an inverse relationship between the chromatin cluster size and the degree of chromatin tethering to the nuclear lamina. We also measured chromatin distribution with respect to the nuclear lamina and found asymmetry of RNAPII distributions within chromatin clusters, which correlated with their proximity to the nuclear envelope, a relationship that is lost in nuclei lacking a functional LINC complex. Our findings demonstrate that chromatin association with the nuclear envelope counteracts chromatin self-attraction and facilitates RNAPII binding to DNA.