MeCP2, a key contributor to neurological disease, activates and represses transcription.
Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of the MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorders, we examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MeCP2. In both models, MeCP2 dysfunction induced changes in the expression levels of thousands of genes, but unexpectedly the majority of genes (approximately 85%) appeared to be activated by MeCP2. We selected six genes and confirmed that MeCP2 binds to their promoters. Furthermore, we showed that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target. These studies suggest that MeCP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription.
Chahrour
Maria
M
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Jung
Sung Yun
SY
Shaw
Chad
C
Zhou
Xiaobo
X
Wong
Stephen T C
ST
Qin
Jun
J
Zoghbi
Huda Y
HY
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007027:Hypothalamic Diseases / Q000235:genetics*; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009422:Nervous System Diseases / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D015518:Rett Syndrome / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors