Investigating transcriptional control of MECP2-BDNF-miR-132 homeostasis network; implicating the role of MeCP2E1/E2 overexpression and metabolic drugs
Date
2021-04-14
Authors
Buist, Marjorie
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Abstract
Rett Syndrome (RTT) and MECP2 Duplication Syndrome (MDS) are caused by mutations in the MECP2 gene encoding “methyl CpG binding protein 2” (MeCP2), a critical epigenetic regulator in the brain. There is no cure available for these diseases, but symptoms have been reversed in mouse models. The two isoforms of the protein, MeCP2E1 and E2 are differentially expressed in the brain and there is increasing evidence that they have unique functions, which is important to consider in developing therapeutic strategies for MeCP2-related disorders. MeCP2 has been shown to function as a transcriptional activator and repressor but the role of each isoform in transcriptional regulation has not been extensively studied. In this study, a new gain-of-function model of MeCP2 isoform-specific overexpression was generated in human brain cells through stable lentiviral transduction. Nascent RNA analysis was performed to test the transcriptional effects of the two isoforms on selected target genes, BDNF and miR-132, which form a homeostasis network with MeCP2, as well as Nucleolin and ribosomal RNAs. Both isoforms were shown to increase nascent BDNF transcripts. The results of the human brain cell line correspond with previous observations in human RTT brain tissues, indicating the model established here could be used in the future for additional screening studies. Small molecule drug screening for RTT therapies has recently focused on metabolic drugs which have the potential to correct metabolic defects in RTT patients as well as cognitive defects. The impact of these drugs on MeCP2 regulation is an important aspect of these studies, since MeCP2 levels are tightly controlled. In this study, the effect of simvastatin and metformin on MECP2 and BDNF transcription was assessed in human brain cells. The results suggested that metformin controls MECP2E1 and BDNF post-transcriptionally, but the effect on MECP2E2 is transcriptional and is a promising drug for RTT. This study highlights the importance of isoform-specific analysis in studies of MeCP2 function and analysis of potential RTT therapies.
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Keywords
MeCP2, Isoforms, BDNF, Transcription, Metformin, Simvastatin