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Genome-wide Analysis of Histone Modifications in Normal Human Islets - Study GBCO3918

Genomics Study Specifications

Study Name Genome-wide Analysis of Histone Modifications in Normal Human Islets
Contact Name Reena Bhandare (Department of Genetics, University of Pennsylvania)
Publication http://www.ncbi.nlm.nih.gov/pubmed/20181961
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Classification Tissue expression, surveys and comparisons
BCBC Release Date July 21, 2010
Public Release Date July 21, 2010
Citation Bhandare R, Schug J, Le Lay J, Fox A, Smirnova O, Liu C, Naji A, Kaestner KH. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res. 2010. 20:428-33
This experiment used ChIP-seq technology to create a genome-wide profile of histone marks in normal human pancreatic islets. In the current work we analyzed two histone marks associated with gene expression (H3K4me3, H3K4me1) and marks associated with gene repression (H3K27me3). Each mark was analyzed using samples obtained from four donors (n=4). Chromatin Immunoprecipitations (ChIPs) for histone marks were performed using specific anti-histone antibodies. Enrichment of each sample was calculated with respect to its individual input using qPCR. Samples were sequenced with Solexa and sequenced DNA from both Input (n=4) and ChIP (n = 4) samples were aligned to the NCBI Genome Build 36.1  Hg18 to determine regions that were enriched for binding by modified histones.
Create a genome-wide map of four histone modifications (H3K4me1, H3K4me2, H3K4me3, and H3K27me3) associated with gene activation or repression in human pancreatic islets.
ChIP-seq technology was used. Chromatin from pancreatic islets was immunoprecipitated with antihistone antibodies to enrich for DNA fragments in regions of the genome associated with modified histones. The precipitated DNA was processed and sequenced using the Illumina Genome Analyzer. Sequenced DNA was aligned to NCBI Genome Build 36.1 (hg18). GLITR was then used to identify enriched regions. A sample of the reads from each histone modification and an equal number of input reads were compared to a large group of input reads collected from a variety of human tissues. FDR of 1.5% was chosen as the cutoff to determine significantly enriched regions. Regions within a certain distance, which varies between 500 and 5000 bp among histone marks, were merged.)
The numbers of significantly enriched regions are 189,103 (H3K4me1), 31,906 (H3K4me2), 36,763 (H3K4me3), and 122,629 (H3K27me3). These enriched regions were merged and annotated by proximity to RefSeqs, Known Genes, and miRNAs. 3826 (16.5%) of the H3K4me3 regions were > 5kbp from the nearest gene, indicating a large number of potentially novel transcriptional start sites active in islets. A large fraction of H3K4me1 (34,994, 24.8%) and H3K4me2 (7762, 24.3%) regions were intergenic and represent potential regulatory regions. Of the 113 previously identified noncoding diabetes-associated single nucleotide polymorphisms SNPs, 18 (15.9%) were within 500 bp of a GLITR H3K4me1 locus, 4 and 2 for H3K4me2 and H3K4me3 respectively. Co-occurance of histone marks was estimated by the coorelation between input-normalized histone modifications near the promoters (0-2 kbp). The correlation is higher between H3K4me2 and H3K4me3 (r=0.735), than H3K4me1 and H3K4me2 (r=0.55), and limited between H3K4me1 and H3K4me3 (r=0.344). H3K27me3 and H3K4me3 tend not to co-occur, with a few exceptions ("bivalent genes", e.g. the HOX gene clusters, including HOXB9 and HOXB7). H3K4 methylation is correlated with gene expression in the presence of CpG island in the promoter.Surprisingly, the highly-transcribed major hormone-encoding genes in the islets (INS and GCG) are not enriched for H3K4me3 while other islet-specific (e.g. PDX1 and MAFB) or house-keeping (e.g. GAPDH) genes are. Comparison of H3K4me3 at gene promoters in human islets and CD+ T-cells revealed a strong correlation for a majority of genes. Nonetheless, enrichment of H3K4me3 at a number of genes appear to be tissue-specific (395 in T-cells and 93 in islets).
The pattern of histone modifications in the islet is complex. The correlation between H3K4me3 and gene expression levels was revealed to be dependent on the presence of CpG islands in the promoter. Promoters containing a CpG island are likely to be methylated at H3K4 regardless of their expression level. On the other hand, many genes, whose promoters are CpG free and not occupied by H3K4me3-modified histones, are highly expressed, such as the two major hormone-producing genes. In contrast to earlier reports, H3K4me3 in some promoters is tissue-specific.
Platform types Histone modification ChIP-Seq, Epigenomic
Platforms Not available
Study Design Type
  • binding_site_identification_design
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Kaestner Lab
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Resource Tags

GAPDH, GCG, H3K27me3, H3K4me1, H3K4me3, HOXB7, HOXB 9, Illumina Genome Analyzer, INS, MAFB, PDX1

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Resource History & Actions

Approved on Jul 21, 2010
Last modified on Jan 17, 2012
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