Transcriptional regulation in pluripotent stem cells by methyl CpG-binding protein 2 (MeCP2)

Rett syndrome (RTT) is one of the most prevalent female mental disorders. De novomutations in methyl CpG-binding protein 2 (MeCP2) are amajor cause of RTT. MeCP2 regulates gene expression as a transcription regu-lator as well as through long-range chromatin interaction. Because MeCP2 is present on the X chromosome, RTT is manifested in an X-linked dominant manner. Investigation using murine MeCP2 null models and post-mortem human brain tissues has contributed to understanding the molecular and physiological function of MeCP2. In addition, RTT models using human induced pluripotent stem cells derived from RTT patients (RTT-iPSCs) provide novel resources to elucidate the regulatory mechanism of MeCP2. Previously, we obtained clones of female RTT-iPSCs that express either wild-type or mutant MECP2 due to the inactivation of one X chromosome. Reactivation of the X chromosome also allowed us to have RTT-iPSCs that express both wild-type and mutantMECP2. Using these unique pluripotent stem cells, we investigated the regulation of gene ex-pression by MeCP2 in pluripotent stem cells by transcriptome analysis. We found that MeCP2 regulates genes encoding mitochondrial membrane proteins. In addition, loss of function in MeCP2 results in de-repres-sion of genes on the inactive X chromosome. Furthermore, we showed that each mutation inMECP2 affects a partly different set of genes. These studies suggest that fundamental cellular physiology is affected by muta-tions inMECP2 from early development, and that a therapeutic approach targeting to unique forms of mutant MeCP2 is needed