TY - JOUR
T1 - Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus
AU - Ben-Shachar, Shay
AU - Chahrour, Maria
AU - Thaller, Christina
AU - Shaw, Chad A.
AU - Zoghbi, Huda Y.
N1 - Funding Information:
This work was funded by NIH/National Institute of Neurological Disorders and Stroke grant NS057819 (H.Z.), National Institute of Child Health and Human Development Mental Retardation and Developmental Disabilities Research Center HD024064 (H.Z.), the International Rett Syndrome Foundation and the Simons Foundation. H.Z. is a Howard Hughes Medical Institute investigator. The microarray data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) (www.ncbi. nlm.nih.gov/geo) and are accessible through GEO Series accession number GSE15574. Funding to pay the Open Access charge was provided by the Howard Hughes Medical Institute.
PY - 2009
Y1 - 2009
N2 - A group of post-natal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression, given that the majority of genes are downregulated upon loss of MeCP2 and upregulated in its presence. To determine if this dual role of MeCP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-g mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MeCP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MeCP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MeCP2 and decreased in its absence, were similarly altered in the hypothalamus. Our data suggest that either gain or loss of MeCP2 results in gene expression changes in multiple brain regions and that some of these changes are global. Further delineation of the expression pattern of MeCP2 target genes throughout the brain might identify subsets of genes that are more amenable to manipulation, and can thus be used to modulate some of the disease phenotypes.
AB - A group of post-natal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression, given that the majority of genes are downregulated upon loss of MeCP2 and upregulated in its presence. To determine if this dual role of MeCP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-g mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MeCP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MeCP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MeCP2 and decreased in its absence, were similarly altered in the hypothalamus. Our data suggest that either gain or loss of MeCP2 results in gene expression changes in multiple brain regions and that some of these changes are global. Further delineation of the expression pattern of MeCP2 target genes throughout the brain might identify subsets of genes that are more amenable to manipulation, and can thus be used to modulate some of the disease phenotypes.
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U2 - 10.1093/hmg/ddp181
DO - 10.1093/hmg/ddp181
M3 - Article
C2 - 19369296
AN - SCOPUS:67249150482
SN - 0964-6906
VL - 18
SP - 2431
EP - 2442
JO - Human molecular genetics
JF - Human molecular genetics
IS - 13
ER -