Control of Pancreas and Liver Gene Expression by HNF Transcription Factors

Odom, Duncan T.; Zizlsperger, Nora; Gordon, D. Benjamin; Bell, George W.; Rinaldi, Nicola; Murray, Heather L.; Volkert, Tom L.; Schreiber, Jörg; Rolfe, P. Alexander; Gifford, David K.; Fraenkel, Ernest; Bell, Graeme I.; Young, Richard A.

doi:10.1126/science.1089769

Cited by 1,206 publications

(1,182 citation statements)

References 30 publications

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“…Major advances have also been made to predict direct targets of a TF by immunoprecipitating and querying the chromatin pulled down with antibodies directed against the specific TF. This technique has the potential to identify individual targets and to construct transcriptional regulatory networks by examining the genome-wide profile of sequences immuno-precipitated by multiple TFs [55].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional control of epidermal specification and differentiation

Dai

Segre

2004

Current Opinion in Genetics & Development

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Recent experiments reveal the role of transcription factors in integrating upstream signals to execute specification and differentiation of epidermal cells. Based on the skin phenotype observed with misregulation of transcription factors such as p63, c-Myc, RelA, pRb, Klf4 and others, their function in controlling proliferation and differentiation is dissected. Understanding the pathways regulated by these factors and their coordinate interactions remains a challenge for the future.

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Section: Discussionmentioning

confidence: 99%

Transcriptional control of epidermal specification and differentiation

Dai

Segre

2004

Current Opinion in Genetics & Development

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“…Early ChIP-chip studies in mammalian genomes utilized various types of PCR amplicon arrays, including arrays tiling a specific genomic region of interest [28], CpG island arrays [29], and promoter arrays [30]. Promoter arrays covering roughly −750 bp to +250 bp relative to transcription start sites have been used to analyze binding of HNF1α, HNF4α, and HNF6 in post-mortem human liver and pancreas [31] and muscle regulatory TFs MyoD, myogenin, and MEF2 in differentiating murine C2C12 skeletal muscle cells [32].…”

Section: Chip-chipmentioning

confidence: 99%

DNA microarray technologies for measuring protein–DNA interactions

Bulyk

2006

Current Opinion in Biotechnology

154

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SummaryDNA binding proteins play key roles in many cellular processes, including transcriptional regulation and replication. Microarray-based technologies permit high-throughput identification of binding sites and functional roles of these proteins. In particular, microarray readout either of chromatin immunoprecipitation ('ChIP-chip') or of DNA adenine methyltransferase fusion proteins ('DamID') enables the identification of in vivo genomic target sites of proteins. A complementary approach, in vitro binding of proteins directly to double-stranded DNA microarrays ('protein binding microarrays'), permits rapid characterization of their DNA binding site sequence specificities. Recent advances in DNA microarray synthesis technologies have permitted the definition of proteins' DNA binding sites at much higher resolution and coverage, and further advances in these and emerging technologies will further increase the efficiencies of these exciting new approaches.

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“…HNF1A is produced in the liver, kidney, intestine and pancreatic islets [5]. It participates in a transcription factor network that regulates pancreatic development as well as fatty acid, protein and carbohydrate metabolism [6]. This network has also been shown to be critically involved in the pathophysiology of type 2 diabetes [7].…”

Section: Introductionmentioning

confidence: 99%

Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-α (HNF1A) function in INS-1 insulinoma cells

et al. 2008

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Aims/hypothesis Mutations in the HNF1A (previously known as TCF1) gene encoding hepatocyte nuclear factor-1α (HNF1A) lead to the development of maturity-onset diabetes of the young, type 3 (HNF1A-MODY), characterised by impaired insulin secretion and a reduction in beta cell mass. HNF1A plays an important role in pancreatic beta cell differentiation and survival. The mammalian target of rapamycin (mTOR) is a central growth factor-and nutrientactivated protein kinase controlling cell metabolism, growth and survival. We investigated the role of mTOR inactivation in the decline in beta cell mass in a cellular model of HNF1A-MODY. Methods Previously we showed that suppression of HNF1A function via expression of a dominant-negative mutant (DN-HNF1A) decreases insulin gene transcription in insulinoma (INS-1) cells. We investigated the signalling of two distinct mTOR protein complexes, mTORC1 and mTORC2, in response to DN-HNF1A induction.Results We observed delayed inactivation of mTORC2 48 h after DN-HNF1A induction, evidenced by a reduction in serine 473 phosphorylation of thymoma viral protooncogene 1 (AKT1). We also observed an early inactivation of mTORC1 24 h after DN-HNF1A induction, which was detected by decreases in threonine 389 phosphorylation of p70 ribosomal protein S6 kinase (S6K1) and serine 65 phosphorylation of translational inhibitor eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). Flow cytometry and gene expression analysis demonstrated a preapoptotic decrease in INS-1 cell size in response to DN-HNF1A induction, and an increase in the level of the mTORC1-regulated cell-cycle inhibitor, cyclin-dependent kinase inhibitor 1B p27. Conclusions/interpretation Our data suggest that mTOR kinase and signalling through mTORC1 are highly sensitive to suppression of HNF1A function, and may contribute to disturbance of cell-size regulation and cell-cycle progression in HNF1A-MODY.

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Control of Pancreas and Liver Gene Expression by HNF Transcription Factors

Cited by 1,206 publications

References 30 publications

Transcriptional control of epidermal specification and differentiation

Transcriptional control of epidermal specification and differentiation

DNA microarray technologies for measuring protein–DNA interactions

Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-α (HNF1A) function in INS-1 insulinoma cells

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