Rett syndrome (RTT) is a severe neurodevelopmental disorder linked to abnormal levels of methyl CpG binding protein 2 (MeCP2), a global transcriptional regulator, known to both enhance and silence gene expression. It has been demonstrated on numerous occasions, however, that replenishing functional MeCP2 levels in the central nervous system, can ameliorate and even reverse the RTT phenotype. One such RTT treatment approach involves administering recombinantly purified MeCP2 while tethered to the cell-penetrating peptide TAT which is known to transduce fused protein cargo across cell membrane as well as the blood-brain barrier. MeCP2 function is imparted through its methyl binding (MBD) and transcriptional repression domains (TRD), which are implicated in protein-DNA and protein-protein interactions respectively. These domains were shown to be crucial for MeCP2 function. In fact has been shown that a truncated MeCP2 construct termed minMeCP2 containing just the MBD and a portion of the TRD can reverse the RTT phenotype just as efficiently as its full-length counterpart in RTT mice. This work further expands on these findings. TAT-minMeCP2 (in fusion with eGFP) has demonstrated superior transduction capabilities into various cell lines compared to the full-length TAT-MeCP2, with subsequent localization to heterochromatic foci in the nucleus. In addition, TAT-minMeCP2 was shown to reverse histone hyperacetylation, a hallmark of RTT pathophysiology more efficiently than its full-length counterpart. These findings further point to the importance that the MeCP2 MBD and TRD in RTT onset and can be built upon, to further enhance MeCP2-based protein replacement therapy development.