Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader-Willi syndrome.
To examine the chromatin basis of imprinting in chromosome 15q11-q13, we have investigated the status of histone acetylation of the SNURF-SNRPN locus, which is a key imprinted gene locus in Prader-Willi syndrome (PWS). Chromatin immunoprecipitation (ChIP) studies revealed that the unmethylated CpG island of the active, paternally derived allele of SNURF-SNRPN was associated with acetylated histones, whereas the methylated maternally derived, inactive allele was specifically hypoacetylated. The body of the SNURF-SNRPN gene was associated with acetylated histones on both alleles. Furthermore, treatment of PWS cells with the DNA methyltransferase inhibitor 5-azadeoxycytidine (5-aza-dC) induced demethylation of the SNURF-SNRPN CpG island and restoration of gene expression on the maternal allele. The reactivation was associated with increased H4 acetylation but not with H3 acetylation at the SNURF-SNRPN CpG island. These findings indicate that (1) a significant role for histone deacetylation in gene silencing is associated with imprinting in 15q11-q13 and (2) silenced genes in PWS can be reactivated by drug treatment.
Saitoh
S
S
Department of Pediatrics, Hokkaido University School of Medicine, Sapporo 060-8638, Japan. ss11@med.hokudai.ac.jp
Wada
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T
D000107:Acetylation / Q000187:drug effects; D000483:Alleles; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002843:Chromatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D018392:Genomic Imprinting / Q000187:drug effects / Q000235:genetics*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D011218:Prader-Willi Syndrome / Q000188:drug therapy / Q000235:genetics*; D011233:Precipitin Tests
D002843:Chromatin; D006657:Histones; D003570:Cytidine Triphosphate; C038673:5-aza-2'-deoxycytidine-5'-triphosphate; D015254:DNA Modification Methylases; D001374:Azacitidine