Core transcriptional regulatory circuitry in human hepatocytes

Odom, Duncan T.; Dowell, Robin D.; Jacobsen, Elizabeth S; Nekludova, Lena; Rolfe, P. Alexander; Danford, Timothy; Gifford, David K.; Fraenkel, Ernest; Bell, Graeme I.; Young, Richard A.

doi:10.1038/msb4100059

Cited by 182 publications

(241 citation statements)

References 38 publications

(55 reference statements)

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“…SNPs rs2021722, rs2763979 and rs2075799 had )log 10 (p-value)>5. SNP rs2021722 is located within TRIM26, which has been found to directly interact with hepatocyte nuclear factor 4-a, whose misregulation contributes to type 2 diabetes [32]. SNP rs2763979 is located within HSPA1B, which also has susceptibility implications in type 2 diabetes [33] and is prevalent in southern Asians [34].…”

Section: Resultsmentioning

confidence: 99%

A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians

Yang

Lin²,

Hsu

et al. 2006

J Biomed Sci

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SummaryGenetic dissection of complex diseases is both important and challenging. The human major histocompatibility complex is involved in many human diseases and genetic mechanisms. This highly polymorphic chromosome region has been extensively studied in Caucasians but not as well in Asians. Thus, we compared genotypic distributions, linkage disequilibria and haplotype blocks between Caucasian and TaiwanÕs Han Chinese populations. Moreover, we investigated the population admixture and phylogenetic system in Han Chinese residing in Taiwan. The results show that TaiwanÕs Han Chinese differ drastically in genotypic information compared with Caucasians but are relatively homogeneous among the three major ethnic subgroups, Minnan, Hakka and Mainlanders. Differences in allele frequency (AF) between Taiwanese and Caucasians in some disease-associated loci may reveal clues to differences in disease prevalence. The results of ethnic heterogeneity imply that public databases should be used with caution in cases where the study population(s) differs from the population characterized in the database. The high homogeneity we observed among the Taiwanese subpopulations mitigates the possibility of spurious association caused by ignoring population stratification in Taiwanese disease gene association studies. These results are useful for understanding our genetic background and designing future disease gene mapping studies.

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Section: Resultsmentioning

confidence: 99%

A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians

Yang

Lin²,

Hsu

et al. 2006

J Biomed Sci

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“…Furthermore, combining genome-wide location and microarray analysis has also helped to reveal the targets of C/EBP beta (CCAAT enhancer-binding protein beta), a basicleucine zipper transcription factor; these targets are critical to the regulation of numerous biological processes, including liver development [18]. These and other findings have demonstrated that a genomic approach is one of the key ways of screening for important candidates that are likely to control hepatocyte differentiation and liver development [19,20].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α

Chen

Pernelle

Tsai³

et al. 2014

Journal of Hepatology

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“…In the adult ␤-cell, the expression of HNF-4␣ is regulated by the pancreatic transcription factor network (21)(22)(23), positively by a number of proteins including the HNF1A, PDX1, and HNF1B gene products (22,24,25) and negatively by itself (21). The key regulatory relationship appears to be that with HNF-1␣ (26).…”

mentioning

confidence: 99%

The Diabetic Phenotype in HNF4A Mutation Carriers Is Moderated By the Expression of HNF4A Isoforms From the P1 Promoter During Fetal Development

Harries

Locke²,

Shields³

et al. 2008

Diabetes

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OBJECTIVE-Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype.RESEARCH DESIGN AND METHODS-We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations.RESULTS-HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4 -6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 vs. 24 years; P ϭ 0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P Ͻ 0.00001).CONCLUSIONS-We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene.

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Core transcriptional regulatory circuitry in human hepatocytes

Cited by 182 publications

References 38 publications

A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians

A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians

Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α

The Diabetic Phenotype in HNF4A Mutation Carriers Is Moderated By the Expression of HNF4A Isoforms From the P1 Promoter During Fetal Development

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