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Mutations in  MECP2  are responsible for the majority of Rett syndrome cases. MECP2 is a regulator of transcription, and has two isoforms, MECP2_e1 and MECP2_e2. There is accumulating evidence that MECP2_e1 is the etiologically relevant variant for Rett. In this study we aim to detect genes that are differentially transcribed in neuronal cells over-expressing either of these two MECP2 isoforms. The human neuroblastoma cell line SK-N-SH was stably infected by lentiviral vectors over-expressing MECP2_e1, MECP2_e2, or eGFP, and were then differentiated into neurons. The same lentiviral constructs were also used to infect mouse Mecp2 knockout (Mecp2 tm1.1Bird ) fibroblasts. RNA from these cells was used for microarray gene expression analysis. For the human neuronal cells, ∼800 genes showed >three-fold change in expression level with the MECP2_e1 construct, and ∼230 with MECP2_e2 (unpaired t-test, uncorrected p value <0.05). We used quantitative RT-PCR to verify microarray results for 41 of these genes. We found significant up-regulation of several genes resulting from over-expression of MECP2_e1 including  SRPX2 ,  NAV3 ,  NPY1R ,  SYN3 , and  SEMA3D .  DOCK8  was shown via microarray and qRT-PCR to be upregulated in both SK-N-SH cells and mouse fibroblasts. Both isoforms up-regulated  GABRA2 ,  KCNA1 ,  FOXG1  and  FOXP2 . Down-regulation of expression in the presence of MECP2_e1 was seen with  UNC5C  and  RPH3A . Understanding the biology of these differentially transcribed genes and their role in neurodevelopment may help us to understand the relative functions of the two MECP2 isoforms, and ultimately develop a better understanding of RTT etiology and determine the clinical relevance of isoform-specific mutations.

Over-Expression of Either MECP2_e1 or MECP2_e2 in Neuronally Differentiated Cells Results in Different Patterns of Gene Expression