Final Report Summary - BOLD (Biology of Liver and Pancreatic Development and Disease)
Most common disorders of western society have multifactorial causes and result from a combination of genetic and environmental influences. Many of those disorders are secondary to dysregulation of fat and sugar metabolism that leads to the “so called” metabolic syndrome of obesity, diabetes, cardiovascular problems, such as heart attacks and stroke, and fatty liver disease. Although there are clear environmental causes such as western diet and alcohol, some individuals and population groups are more likely to develop severe illness than others.
BOLD partners are investigating the influences of transcriptional gene networks that are crucial for the development of Liver and Pancreas, which are the key “metabolic organs” producing hormones and enzymes that govern the complex regulation of lipid and carbohydrate metabolism.
The research programme in BOLD was underpinned by an innovative approach to the study of Liver and Pancreatic Disorders (LPD) using cutting edge technology and made advances in the current ‘state of the art’, such as the understanding of cellular changes that predispose to pancreatic cancer and genetic changes that lead to diabetes.
BOLD capitalized on involvement of excellent quality researchers from private and public sectors some of whom were not previously involved in LPD research. All these steps ensured that BOLD produced new researchers able to develop into world leaders in the field, both in academia and in industry.
The BOLD Network consists of 10 partners from 8 European countries hosting the training of 15 early stage researchers and 3 experienced researchers from throughout Europe, Asia and South America. The training in task-specific and generic and transferable research skills is tailored towards the Fellows’ needs.
What have we found?
The scientific highlights from the four years of the Network include:
1. A discovery by that specific Sox and HNF transcription factors are involved in the initial changes of pancreatic cancer (Partner DDI) (publication “Gut”)
Prévot PP, Simion A, Grimont A, Colletti M, Khalaileh A, Van den Steen G, Sempoux C, Xu X, Roelants V, Hald J, Bertrand L, Heimberg H, Konieczny SF, Dor Y, Lemaigre FP, and Jacquemin P. Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia. Gut, 61, 1723-1732, 2012.
2. Building of a comprehensive map of genetic networks involved in the control of liver metabolic function has been carefully detailed (Partner AF, published in “Science”)
Schmidt D, Wilson MD, Ballester B, Schwalie PC, Brown GD, Marshall A, Kutter C, Watt S, Martinez-Jimenez CP, Mackay S, Talianidis I, Flicek P, Odom DT. Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science. 2010 328:1036-40.
3. Identification of a novel biomarker of early pancreatic cancer (Partner IDIBAPS) that will help to treat the disease early (Gene Development publication).
van Arensbergen J, García-Hurtado J, Maestro MA, Correa-Tapia M, Rutter GA, Vidal M, Ferrer J. Ring1b bookmarks genes in pancreatic embryonic progenitors for repression in adult β cells. Genes Dev. 27:52-63. 2013.
4. A discovery of the pancreatic islet specific enhancer elements that were then validated in zebrafish was a collaboration between BOLD Partners IDIBAPS and UB and was published in Nature Genetics.
Pasquali L, Gaulton KJ, Rodríguez-Seguí SA, Mularoni L, Miguel-Escalada I, Akerman I, Tena JJ, Morán I, Gómez-Marín C, van de Bunt M, Ponsa-Cobas J, Castro N, Nammo T, Cebola I, García-Hurtado J, Maestro MA, Pattou F, Piemonti L, Berney T, Gloyn AL, Ravassard P, Skarmeta JL, Müller F, McCarthy MI, Ferrer J. Nat Genet. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. 2014 Jan 12. doi: 10.1038/ng.2870 PMID: 24413736
Pasquali, L., Rodríguez-Seguí, S., Miguel-Escalada, I., Mularoni, L., Akerman, I/. van de Bunt, M., Tena, J.J. Morán, I., Nammo, T., Cebola, I., García-Hurtado, J., Castro, N., Angel Maestro, M., Jose, R., Pattou, F., Kerr-Conte, J., Piemonti, L., Nano, R., Berney, T., Gloyn, A., Ravassard, P., Gomez Skarmeta, JL., Müller, F., McCarthy, M, and Ferrer J. Deconstructing the epigenomic and cis-regulatory code of human pancreatic islet-cells. Nat. Genet, (2014) Jan 12. doi: 10.1038/ng.2870.
5. Collaboration between BOLD Partners IDIBAPS and UNIEXE resulted in several discoveries of novel genes involved in pancreatic diseases including the finding of mutations in PTF1A that was published in Nature Genetics.
Weedon MN, Cebola I, Patch AM, Flanagan SE, De Franco E, Caswell R, Rodríguez-Seguí SA, Shaw-Smith C, Cho CH, Lango Allen H, Houghton JA, Roth CL, Chen R, Hussain K, Marsh P, Vallier L, Murray A; International Pancreatic Agenesis Consortium, Ellard S, Ferrer J, Hattersley AT. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat Genet. 2014 46:61-4.
6. A collaboration between Partners AF and CRUK resulted in a discovery of transcription factors important in liver development and disease, which was published in Cell.
Klara Stefflova, David Thybert, Michael D. Wilson, Ian Streeter, Jelena Aleksic, Panagiota Karagianni, Alvis Brazma, David J. Adams, Iannis Talianidis, John C. Marioni, Paul Flicek, and Duncan T. Odom. Cooperativity and Rapid Evolution of Cobound Transcription Factors in Closely Related Mammals. Cell. 154, 530–540. 2013.
7. A collaboration between Partners UB, KIT, Acureomics and Associate Partner Acurepharma resulted in development of methods for drug screening in liver diseases using zebrafish, which led to 2 published manuscripts.
Dhillon SS, Dóró E, Magyary I, Egginton S, Sík A and Müller F. Optimisation of embryonic and larval ECG measurement in zebrafish for quantifying the effect of QT prolonging drugs. PLoS One. 8:e60552. 2013. (impact factor 3.7).
Feula, A,. Dhillon, SS. Byravan, M. Sangha, R. Ebanks, M. H. Salih, N. Spencer, L. Male, I. Magyary, W.-P. Deng, F. Müller and J. S. Fossey. Org. Biomol. Chem. 11:5083-93. 2013. (impact factor 3.5).
8. Overall 38 manuscripts have been published as a direct result of BOLD including 10 published in the very highest impact factor journals: Cell, Nature, Science and Nature Genetics.
BOLD has made excellent progress in achieving all the goals set for the 4 years of the Project.
The final BOLD meeting was organized in Athens that coincided with an international conference on Liver and Pancreatic Development and Disease co-organized by Iannis Talianidis (Research Lead at BOLD) and Frederic Lemaigre (Training Lead at BOLD) and funded by EMBO (European Molecular Biology Organisation). BOLD fellows were able to disseminate their research via talks and posters to a wide European audience of experts in liver development and disease. Fellows enjoyed the atmosphere of the workshop and conference and the presentations were of exceptional quality. All partners and Fellows have presented extensively at various national and international meetings where the BOLD research and training programme was advertised.
A video was made at this meeting featuring several of the Fellows and is featured on the BOLD website which will stay active for a further year. This video gives an insight into what the Fellows got from the Network and what they saw as the highlights from working on BOLD. The main advantages were collaborations made with other laboratories through the Network and network events and they thought that working on BOLD would have a positive impact on their future careers.
How might our results be useful?
Work conducted by the BOLD network has implications for:
• Understanding how important metabolic organs: Liver and Pancreas develop
• Deciphering the molecular pathways that go wrong in metabolic diseases
• Developing new approaches to making accurate diagnosis in patients with metabolic diseases
• Making medicines personalized for individual patients
To promote the application of our findings, we work with a number of industrial partners including:
Acurepharma, Acureomics and Maveric.
Three patent applications are being drafted and filed. These are regarding Metabolic pattern, In silico tox screening and In silico inflammatory agent screening.
The BOLD website can be www.boldmcitn.eu
BOLD partners are investigating the influences of transcriptional gene networks that are crucial for the development of Liver and Pancreas, which are the key “metabolic organs” producing hormones and enzymes that govern the complex regulation of lipid and carbohydrate metabolism.
The research programme in BOLD was underpinned by an innovative approach to the study of Liver and Pancreatic Disorders (LPD) using cutting edge technology and made advances in the current ‘state of the art’, such as the understanding of cellular changes that predispose to pancreatic cancer and genetic changes that lead to diabetes.
BOLD capitalized on involvement of excellent quality researchers from private and public sectors some of whom were not previously involved in LPD research. All these steps ensured that BOLD produced new researchers able to develop into world leaders in the field, both in academia and in industry.
The BOLD Network consists of 10 partners from 8 European countries hosting the training of 15 early stage researchers and 3 experienced researchers from throughout Europe, Asia and South America. The training in task-specific and generic and transferable research skills is tailored towards the Fellows’ needs.
What have we found?
The scientific highlights from the four years of the Network include:
1. A discovery by that specific Sox and HNF transcription factors are involved in the initial changes of pancreatic cancer (Partner DDI) (publication “Gut”)
Prévot PP, Simion A, Grimont A, Colletti M, Khalaileh A, Van den Steen G, Sempoux C, Xu X, Roelants V, Hald J, Bertrand L, Heimberg H, Konieczny SF, Dor Y, Lemaigre FP, and Jacquemin P. Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia. Gut, 61, 1723-1732, 2012.
2. Building of a comprehensive map of genetic networks involved in the control of liver metabolic function has been carefully detailed (Partner AF, published in “Science”)
Schmidt D, Wilson MD, Ballester B, Schwalie PC, Brown GD, Marshall A, Kutter C, Watt S, Martinez-Jimenez CP, Mackay S, Talianidis I, Flicek P, Odom DT. Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science. 2010 328:1036-40.
3. Identification of a novel biomarker of early pancreatic cancer (Partner IDIBAPS) that will help to treat the disease early (Gene Development publication).
van Arensbergen J, García-Hurtado J, Maestro MA, Correa-Tapia M, Rutter GA, Vidal M, Ferrer J. Ring1b bookmarks genes in pancreatic embryonic progenitors for repression in adult β cells. Genes Dev. 27:52-63. 2013.
4. A discovery of the pancreatic islet specific enhancer elements that were then validated in zebrafish was a collaboration between BOLD Partners IDIBAPS and UB and was published in Nature Genetics.
Pasquali L, Gaulton KJ, Rodríguez-Seguí SA, Mularoni L, Miguel-Escalada I, Akerman I, Tena JJ, Morán I, Gómez-Marín C, van de Bunt M, Ponsa-Cobas J, Castro N, Nammo T, Cebola I, García-Hurtado J, Maestro MA, Pattou F, Piemonti L, Berney T, Gloyn AL, Ravassard P, Skarmeta JL, Müller F, McCarthy MI, Ferrer J. Nat Genet. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. 2014 Jan 12. doi: 10.1038/ng.2870 PMID: 24413736
Pasquali, L., Rodríguez-Seguí, S., Miguel-Escalada, I., Mularoni, L., Akerman, I/. van de Bunt, M., Tena, J.J. Morán, I., Nammo, T., Cebola, I., García-Hurtado, J., Castro, N., Angel Maestro, M., Jose, R., Pattou, F., Kerr-Conte, J., Piemonti, L., Nano, R., Berney, T., Gloyn, A., Ravassard, P., Gomez Skarmeta, JL., Müller, F., McCarthy, M, and Ferrer J. Deconstructing the epigenomic and cis-regulatory code of human pancreatic islet-cells. Nat. Genet, (2014) Jan 12. doi: 10.1038/ng.2870.
5. Collaboration between BOLD Partners IDIBAPS and UNIEXE resulted in several discoveries of novel genes involved in pancreatic diseases including the finding of mutations in PTF1A that was published in Nature Genetics.
Weedon MN, Cebola I, Patch AM, Flanagan SE, De Franco E, Caswell R, Rodríguez-Seguí SA, Shaw-Smith C, Cho CH, Lango Allen H, Houghton JA, Roth CL, Chen R, Hussain K, Marsh P, Vallier L, Murray A; International Pancreatic Agenesis Consortium, Ellard S, Ferrer J, Hattersley AT. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat Genet. 2014 46:61-4.
6. A collaboration between Partners AF and CRUK resulted in a discovery of transcription factors important in liver development and disease, which was published in Cell.
Klara Stefflova, David Thybert, Michael D. Wilson, Ian Streeter, Jelena Aleksic, Panagiota Karagianni, Alvis Brazma, David J. Adams, Iannis Talianidis, John C. Marioni, Paul Flicek, and Duncan T. Odom. Cooperativity and Rapid Evolution of Cobound Transcription Factors in Closely Related Mammals. Cell. 154, 530–540. 2013.
7. A collaboration between Partners UB, KIT, Acureomics and Associate Partner Acurepharma resulted in development of methods for drug screening in liver diseases using zebrafish, which led to 2 published manuscripts.
Dhillon SS, Dóró E, Magyary I, Egginton S, Sík A and Müller F. Optimisation of embryonic and larval ECG measurement in zebrafish for quantifying the effect of QT prolonging drugs. PLoS One. 8:e60552. 2013. (impact factor 3.7).
Feula, A,. Dhillon, SS. Byravan, M. Sangha, R. Ebanks, M. H. Salih, N. Spencer, L. Male, I. Magyary, W.-P. Deng, F. Müller and J. S. Fossey. Org. Biomol. Chem. 11:5083-93. 2013. (impact factor 3.5).
8. Overall 38 manuscripts have been published as a direct result of BOLD including 10 published in the very highest impact factor journals: Cell, Nature, Science and Nature Genetics.
BOLD has made excellent progress in achieving all the goals set for the 4 years of the Project.
The final BOLD meeting was organized in Athens that coincided with an international conference on Liver and Pancreatic Development and Disease co-organized by Iannis Talianidis (Research Lead at BOLD) and Frederic Lemaigre (Training Lead at BOLD) and funded by EMBO (European Molecular Biology Organisation). BOLD fellows were able to disseminate their research via talks and posters to a wide European audience of experts in liver development and disease. Fellows enjoyed the atmosphere of the workshop and conference and the presentations were of exceptional quality. All partners and Fellows have presented extensively at various national and international meetings where the BOLD research and training programme was advertised.
A video was made at this meeting featuring several of the Fellows and is featured on the BOLD website which will stay active for a further year. This video gives an insight into what the Fellows got from the Network and what they saw as the highlights from working on BOLD. The main advantages were collaborations made with other laboratories through the Network and network events and they thought that working on BOLD would have a positive impact on their future careers.
How might our results be useful?
Work conducted by the BOLD network has implications for:
• Understanding how important metabolic organs: Liver and Pancreas develop
• Deciphering the molecular pathways that go wrong in metabolic diseases
• Developing new approaches to making accurate diagnosis in patients with metabolic diseases
• Making medicines personalized for individual patients
To promote the application of our findings, we work with a number of industrial partners including:
Acurepharma, Acureomics and Maveric.
Three patent applications are being drafted and filed. These are regarding Metabolic pattern, In silico tox screening and In silico inflammatory agent screening.
The BOLD website can be www.boldmcitn.eu