Pancreatic genetics

The aim of the Pancreatic genetic group is to identify the RNA signalling and regulation network and the genetic variants that control pancreas development, and to explore their involvement in the onset of metabolic disorders such as diabetes.

We combine human-induced pluripotent stem cells with functional studies and genomic analyses to further understand how genetics drive differences between individuals in the context of metabolic disorders.

[Richard Gieseck III]

Background

Diabetes is a growing health problem around the world, with 28 million people estimated to have type 1 diabetes and 10 times more people with type 2 diabetes.

Growing evidences have suggested a strong genetic influence in the onset of diabetes. Accordingly, genome-wide association studies have identified loci associated with diabetes and related metabolic disorders. Several of these genetic variants are linked with genes potentially involved in early development of the pancreas; suggesting that developmental mechanisms could be relevant in adult disease. However, to develop new therapeutic approaches, we need to conduct functional studies to validate our findings.

The group aims to further understand how genetics drive differences between individuals in the context of metabolic disorders by combining human-induced pluripotent stem cells, functional studies and genomic analyses.

Research

Our group uses hIPSCs (human-induced pluripotent stem cells) to perform functional studies on genes involved in early development of the pancreas and liver. These functional studies are performed on a large cohort of hIPSC lines and combined with genome-wide analyses such as RNA-sequencing and ChIP-Sequencing. This approach enables us to uncover the transcriptional networks and the genetic mechanisms controlling early pancreatic development.

Furthermore, we are using genetic modifications to correct or to impose genetic variants in different background to determine their influence on cellular phenotype especially on the capacity of pancreatic progenitors to generate endocrine cells.

We have a number of ongoing projects, including:

HipSci (Human-Induced Pluripotent Stem Cells Initiative)

HipSci brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. Between 2013 and 2016 we aim to generate iPS cells from more than 700 healthy individuals and 800 individuals with genetic disease. We will then use these cells to discover how genomic variation impacts on cellular phenotype and identify new disease mechanisms.

Pancreatic genetics

The goal of this project is to uncover mechanisms connecting pancreatic development and metabolic disorders by identifying new genes and epigenetic marks controlling endocrine cell production. This project is run in close collaboration with the newly created Cellular Genetics and Phenotyping platform at the Sanger Institute and will aim to use over 100 hIPSC lines generated by the HipSci consortium to perform genetic studies.

Collaborations

We are part of the HipSci (Human-Induced Pluripotent Stem Cells Initiative)

On campus, we work closely with the following Sanger Institute faculty members:

Selected Publications

  • Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells.

    Cho CH, Hannan NR, Docherty FM, Docherty HM, Joåo Lima M, Trotter MW, Docherty K and Vallier L

    Diabetologia 2012;55;12;3284-95

    PUBMED: 23011350; PMC: 3483105; DOI: 10.1007/s00125-012-2687-x

  • Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells.

    Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordóñez A, Hannan NR, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA, Bradley A and Vallier L

    Nature 2011;478;7369;391-4

    PUBMED: 21993621; PMC: 3198846; DOI: 10.1038/nature10424

  • Activin/Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors.

    Brown S, Teo A, Pauklin S, Hannan N, Cho CH, Lim B, Vardy L, Dunn NR, Trotter M, Pedersen R and Vallier L

    Stem cells (Dayton, Ohio) 2011;29;8;1176-85

    PUBMED: 21630377; DOI: 10.1002/stem.666

  • Pluripotency factors regulate definitive endoderm specification through eomesodermin.

    Teo AK, Arnold SJ, Trotter MW, Brown S, Ang LT, Chng Z, Robertson EJ, Dunn NR and Vallier L

    Genes & development 2011;25;3;238-50

    PUBMED: 21245162; PMC: 3034899; DOI: 10.1101/gad.607311

  • Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells.

    Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA and Vallier L

    The Journal of clinical investigation 2010;120;9;3127-36

    PUBMED: 20739751; PMC: 2929734; DOI: 10.1172/JCI43122

  • Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development.

    Touboul T, Hannan NR, Corbineau S, Martinez A, Martinet C, Branchereau S, Mainot S, Strick-Marchand H, Pedersen R, Di Santo J, Weber A and Vallier L

    Hepatology (Baltimore, Md.) 2010;51;5;1754-65

    PUBMED: 20301097; DOI: 10.1002/hep.23506

  • SIP1 mediates cell-fate decisions between neuroectoderm and mesendoderm in human pluripotent stem cells.

    Chng Z, Teo A, Pedersen RA and Vallier L

    Cell stem cell 2010;6;1;59-70

    PUBMED: 20074535; DOI: 10.1016/j.stem.2009.11.015

Team

No team members listed

* quick link - http://q.sanger.ac.uk/pancreat