MeCP2 interacts with the super elongation complex to regulate transcription

Loss-of-function mutations in methyl-CpG binding protein 2 (<i>MECP2</i>) cause Rett syndrome. While we know that MeCP2 binds to methylated cytosines on DNA, the full breadth of the molecular mechanisms by which MeCP2 regulates gene expression remains incompletely understood. Here, using a genetic modifier screen, we identify the super elongation complex, a P-TEFb-containing elongation factor that releases promoter-proximally paused RNA polymerase II, as a genetic interactor of <i>MECP2</i>. MeCP2 physically interacts with SEC subunits and directly binds AFF4, the scaffold of the SEC, via the transcriptional repression domain. Furthermore, MeCP2 facilitates the binding of AFF4 on a subset of genes in the mouse brain regulating synaptic plasticity and concordantly promotes the binding of RNA polymerase II on these genes. Last, while haploinsufficiency of <i>Aff4</i> does not exhibit any behavioral deficits in mice, it exacerbates the impaired contextual learning behavior of <i>Mecp2</i> hypomorphic mice. We propose a previously unknown mechanism by which MePC2 regulates gene expression underlying synaptic plasticity.