A Hox-dependent anchoring mechanism mediates transcriptional repression of autophagy-related genes at the nuclear periphery

Abstract

The spatial organization of the genome within the nucleus is critical for gene regulation, yet the mechanisms by which transcription factors (TFs) orchestrate this process remain poorly understood. Here, we demonstrate that the Drosophila Hox protein Ultrabithorax (Ubx) represses autophagy-related (atg) genes by tethering their loci to the nuclear periphery. This repressive activity relies on the interaction with the nuclear lamina component Lamin-C (LamC). Furthermore, we identify that DNA-binding of Ubx is determinant for both the physical interaction with nucleoplasmic LamC and the repression of atg genes in vivo. Together, our findings reveal a mechanism whereby a Hox TF functions as a spatial anchor, positioning target genes within a LamC-rich nuclear compartment to ensure efficient transcriptional repression.