Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome.
Mutations in MECP2 are associated with Rett syndrome, an X-linked neurodevelopmental disorder. To identify genes targeted by Mecp2, we sequenced 100 in vivo Mecp2-binding sites in mouse brain. Several sequences mapped to an imprinted gene cluster on chromosome 6, including Dlx5 and Dlx6, whose transcription was roughly two times greater in brains of Mecp2-null mice compared with those of wild-type mice. The maternally expressed gene DLX5 showed a loss of imprinting in lymphoblastoid cells from individuals with Rett syndrome. Because Dlx5 regulates production of enzymes that synthesize gamma-aminobutyric acid (GABA), loss of imprinting of Dlx5 may alter GABAergic neuron activity in individuals with Rett syndrome. In mouse brain, Dlx5 imprinting was relaxed, yet Mecp2-mediated silent-chromatin structure existed at the Dlx5-Dlx6 locus in brains of wild-type, but not Mecp2-null, mice. Mecp2 targeted histone deacetylase 1 to a sharply defined, approximately 1-kb region at the Dlx5-Dlx6 locus and promoted repressive histone methylation at Lys9 at this site. Chromatin immunoprecipitation-combined loop assays showed that Mecp2 mediated the silent chromatin-derived 11-kb chromatin loop at the Dlx5-Dlx6 locus. This loop was absent in chromatin of brains of Mecp2-null mice, and Dlx5-Dlx6 interacted with far distant sequences, forming distinct active chromatin-associated loops. These results show that formation of a silent-chromatin loop is a new mechanism underlying gene regulation by Mecp2.
Horike
Shin-ichi
S
Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mail Stop 84-171, University of California, Berkeley, California 94720, USA.
Cai
Shutao
S
Miyano
Masaru
M
Cheng
Jan-Fang
JF
Kohwi-Shigematsu
Terumi
T
D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D018899:CpG Islands / Q000502:physiology; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D018392:Genomic Imprinting; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D051379:Mice; D005810:Multigene Family; D009474:Neurons / Q000378:metabolism; D011233:Precipitin Tests; D012097:Repressor Proteins / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics*; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C100596:DLX5 protein, human; D004268:DNA-Binding Proteins; C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; D018398:Homeodomain Proteins; C497392:MECP2 protein, human; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid