Endocrine Regulatory Genomics

  • Lorenzo Group
+34 935 572 813
ICO - German Trias i Pujol

Edifici IMPPC
Institut de Medicina Predictiva i
Personalitzada del Càncer
Ctra. de Can Ruti, camí de les escoles, s/n
08916 Badalona (Barcelona) - Spain

Lab 1-20 Office 3(first floor)

 

 

Directions

Summary

The endocrine system consists of a collection of distinct cell identities organized in tissues and shaped into functional organs. These highly specialized tissues ensure the physiological equilibrium of an organism and its possibility, throughout life, to interact with the environment.

How do these cell populations preserve their identity? Which molecular mechanisms are required to maintain their phenotype stable for decades? How are gene regulatory networks altered in pathological conditions?

Our group combines molecular genetics and bioinformatic approaches to understand the regulatory mechanisms that control function and cell fate of the endocrine tissues central to diabetes.

Our group is also contributing to the insulin-producing beta-cellsregulatory genomics by maintaining and developing the “islet regulome browser” a web tool that allows the visualization of different classes of regulatory elements, together with enhancer clusters, transcription factor binding sites, and binding motifs in human pancreatic islets.

www.isletregulome.com

Research

Main lines of research:

  • unmasking the regulatory networks, in the insulin-producing pancreatic beta-cells, that prelude the onset of different forms of diabetes.
  • identifying the regulatory changes underlying theloss of cell fate in neoplastic conditions such as in the neuroendocrine tumors.

People

Selected publications

Mularoni L, Ramos-Rodríguez M, Pasquali L

The Pancreatic Islet Regulome Browser.

Front Genet 2017, 8 13. Epub 14 Feb 2017
The pancreatic islet is a highly specialized tissue embedded in the exocrine pancreas whose primary function is that of controlling glucose homeostasis. Thus, understanding the transcriptional control of islet-cell may help to puzzle out the pathogenesis of glucose metabolism disorders. Integrative computational analyses of transcriptomic and epigenomic data allows predicting genomic coordinates of putative regulatory elements across the genome and, decipher tissue-specific functions of the non-coding genome. We herein present the Islet Regulome Browser, a tool that allows fast access and exploration of pancreatic islet epigenomic and transcriptomic data produced by different labs worldwide. The Islet Regulome Browser is now accessible on the internet or may be installed locally. It allows uploading custom tracks as well as providing interactive access to a wealth of information including Genome-Wide Association Studies (GWAS) variants, different classes of regulatory elements, together with enhancer clusters, stretch-enhancers and transcription factor binding sites in pancreatic progenitors and adult human pancreatic islets. Integration and visualization of such data may allow a deeper understanding of the regulatory networks driving tissue-specific transcription and guide the identification of regulatory variants. We believe that such tool will facilitate the access to pancreatic islet public genomic datasets providing a major boost to functional genomics studies in glucose metabolism related traits including diabetes.
Més informació
Cebola I, Pasquali L

Non-coding genome functions in diabetes.

J. Mol. Endocrinol. 5 Oct 2015, . Epub 5 Oct 2015
Most of the genetic variation associated with diabetes, through genome-wide association studies, does not reside in protein-coding regions, making the identification of functional variants and their eventual translation to the clinic challenging. In recent years, high-throughput sequencing-based methods have enabled genome-scale high-resolution epigenomic profiling in a variety of human tissues, allowing the exploration of the human genome outside of the well-studied coding regions. These experiments unmasked tens of thousands of regulatory elements across several cell types, including diabetes-relevant tissues, providing new insights into their mechanisms of gene regulation. Regulatory landscapes are highly dynamic and cell type-specific, and, being sensitive to DNA sequence variation, can vary with individual genomes. The scientific community is now in place to exploit the regulatory maps of tissues central to diabetes etiology, such as pancreatic progenitors and adult islets. This giant leap forward in the understanding of pancreatic gene regulation is revolutionizing our capacity to discriminate between functional and non-functional noncoding variants, opening opportunities to uncover regulatory links between sequence variation and diabetes susceptibility. In this review, we focus on the noncoding regulatory landscape of the pancreatic endocrine cells, and provide an overview of the recent developments in this field.
Més informació
Horikoshi M, Pasquali L, Wiltshire S, Huyghe JR, Mahajan A, Asimit JL, Ferreira T, Locke AE, Robertson NR, Wang X, Sim X, Fujita H, Hara K, Young R, Zhang W, Choi S, Chen H, Kaur I, Takeuchi F, Fontanillas P, Thuillier D, Yengo L, Below JE, Tam CH, Wu Y, Abecasis G, Altshuler D, Bell GI, Blangero J, Burtt NP, Duggirala R, Florez JC, Hanis CL, Seielstad M, Atzmon G, Chan JC, Ma RC, Froguel P, Wilson JG, Bharadwaj D, Dupuis J, Meigs JB, Cho YS, Park T, Kooner JS, Chambers JC, Saleheen D, Kadowaki T, Tai ES, Mohlke KL, Cox NJ, Ferrer J, Zeggini E, Kato N, Teo YY, Boehnke M, McCarthy MI, Morris AP

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms.

Hum. Mol. Genet. 15 Mai 2016, 25 (10) 2070-2081. Epub 23 Feb 2016
To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.
Més informació
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, Gómez-Skarmeta JL, Müller F, McCarthy MI, Ferrer J

Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants.

Nat. Genet. Feb 2014, 46 (2) 136-43. Epub 12 Gen 2014
Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.
Més informació
Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, Panhuis TM, Mieczkowski P, Secchi A, Bosco D, Berney T, Montanya E, Mohlke KL, Lieb JD, Ferrer J

A map of open chromatin in human pancreatic islets.

Nat. Genet. Mar 2010, 42 (3) 255-9. Epub 31 Gen 2010
Tissue-specific transcriptional regulation is central to human disease. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). We identified approximately 80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed approximately 3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility.
Més informació
Show all publications

Current projects

Dynamics of the epigenetic regulation the pancreatic islets cells and diabetes

Responsable:Lorenzo Pasquali
Codi:BFU2014-58150-R
Financiadors:
Data d'inici:01/10/2015
Data de finalització:31/12/2017

Ramon y Cajal

Responsable:Lorenzo Pasquali
Codi:RYC-2013-12864
Financiadors:
Data d'inici:11/11/2015
Data de finalització:11/11/2019

Identification of type 2 diabetes target genes

Responsable:Lorenzo Pasquali
Financiadors:
Data d'inici:01/04/2014
Data de finalització:01/04/2016

Beta-cells cis-regulatory networks and Type 1 Diabetes

Responsable:Lorenzo Pasquali
Codi:201624.10
Financiadors:
  • Marató de TV3
Data d'inici:07/03/2017
Data de finalització:07/03/2020

Impacto de la hormona GLP1 sobre la regulación genómica de los islotes pancreáticos humanos.

Responsable:Lorenzo Pasquali
Codi:201624.10
Financiadors:
  • SED
Data d'inici:01/06/2017
Data de finalització:01/06/2018