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- Wallerman, Ola, et al.
(författare)
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Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing
- 2009
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 37:22, s. 7498-7508
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression is regulated by combinations of transcription factors, which can be mapped to regulatory elements on a genome-wide scale using ChIP experiments. In a previous ChIP-chip study of USF1 and USF2 we found evidence also of binding of GABP, FOXA2 and HNF4a within the enriched regions. Here, we have applied ChIP-seq for these transcription factors and identified 3064 peaks of enrichment for GABP, 7266 for FOXA2 and 18783 for HNF4a. Distal elements with USF2 signal was frequently bound also by HNF4a and FOXA2. GABP peaks were found at transcription start sites, whereas 94% of FOXA2 and 90% of HNF4a peaks were located at other positions. We developed a method to accurately define TFBS within peaks, and found the predicted sites to have an elevated conservation level compared to peak centers; however the majority of bindings were not evolutionary conserved. An interaction between HNF4a and GABP was seen at TSS, with one-third of the HNF4a positive promoters being bound also by GABP, and this interaction was verified by co-immunoprecipitations.
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| 3. |
- Bysani, Madhu Sudhan Reddy, et al.
(författare)
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ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancer
- 2013
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 6, s. 50-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Steatohepatitis occurs in alcoholic liver disease and may progress to liver cirrhosis and hepatocellular carcinoma. Its molecular pathogenesis is to a large degree unknown. Histone modifications play a key role in transcriptional regulations as marks for silencing and activation of gene expression and as marks for functional elements. Many transcription factors (TFs) are crucial for the control of the genes involved in metabolism, and abnormality in their function may lead to disease. Methods: We performed ChIP-seq of the histone modifications H3K4me1, H3K4me3 and H3K27ac and a candidate transcription factor (USF1) in liver tissue from patients with steatohepatitis and normal livers and correlated results to mRNA-expression and genotypes. Results: We found several regions that are differentially enriched for histone modifications between disease and normal tissue, and qRT-PCR results indicated that the expression of the tested genes strongly correlated with differential enrichment of histone modifications but is independent of USF1 enrichment. By gene ontology analysis of differentially modified genes we found many disease associated genes, some of which had previously been implicated in the etiology of steatohepatitis. Importantly, the genes associated to the strongest histone peaks in the patient were over-represented in cancer specific pathways suggesting that the tissue was on a path to develop to cancer, a common complication to the disease. We also found several novel SNPs and GWAS catalogue SNPs that are candidates to be functional and therefore needs further study. Conclusion: In summary we find that analysis of chromatin features in tissue samples provides insight into disease mechanisms.
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| 5. |
- Wallerman, Ola, et al.
(författare)
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Nucleosome landscape in HepG2 cells in relation to NFY, HNF4a and FOXA2 binding sites
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Nucleosomes are the building blocks that compact the DNA in the nucleus, thereby regulating its accessibility. Here we report a genome-wide nucleosome positioning analysis on the HepG2 cell line, based on deep sequencing of mononucleosomal DNA. In concordance with other studies, we found nucleosomes to be well positioned at the TSS, with a nucleosome free region in the proximal promoter. Focusing on the importance of nucleosomal positioning at distal elements we found that TFBS sites often are flanked by well-positioning nucleosomes at a distance that indicate that the TF complexes replaces the nucleosome, and we also find that some transposable elements have distinct nucleosomal signatures. To build on previous regulatory data for HepG2 cells we also produced ChIP-seq reads for the transcription factors NF-Y and TCF7L2 and correlate this to the HepG2 transcriptome as defined by RNA-seq and Pol-II ChIP-seq. NF-Y was found primarily at promoters, contrary to what has been suggested from previous studies, and binds genes involved in cell cycle and chromatin organization.
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