LEDGF interacts with the NID of MeCP2 and modulates MeCP2 condensates

Methyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed nuclear protein that is involved in transcriptional regulation and chromatin remodeling. MeCP2 exists in two isoforms, MeCP2 E1 and MeCP2 E2, which share the same functional domains. Loss-of-function mutations in the MeCP2 gene are the main cause of Rett syndrome (RTT). Previous studies identified a direct interaction between MeCP2 and Lens Epithelium-derived Growth Factor (LEDGF), a transcriptional regulator that also exists in two isoforms, LEDGF/p75 and LEDGF/p52. Here, we further characterized the molecular and functional interaction between MeCP2 and LEDGF. The NID domain in MeCP2 is crucial for the binding to the PWWP-CR1 region of LEDGF. Introduction of R306C, a known RTT mutation in the NID of MeCP2, reduced the interaction with LEDGF. Our data reveal mutual inhibition of MeCP2 and LEDGF multimerization due to overlapping binding sites. In line with this observation, LEDGF depletion resulted in enlarged MeCP2 and heterochromatin condensates in NIH3T3 cells. Unraveling the molecular interaction and functional impact of the MeCP2-LEDGF interaction will increase our understanding of RTT pathogenesis.