Novel Pancreatic Endocrine Maturation Pathways Identified by Genomic Profiling and Causal Reasoning

• Published in: PloS one Vol. 8; no. 2; p. e56024
• Main Authors: Gutteridge, Alex, Rukstalis, J. Michael, Ziemek, Daniel, Tié, Mark, Ji, Lin, Ramos-Zayas, Rebeca, Nardone, Nancy A., Norquay, Lisa D., Brenner, Martin B., Tang, Kim, McNeish, John D., Rowntree, Rebecca K.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.02.2013; Public Library of Science (PLoS)
• Subjects: Algorithms; Animals; Bioinformatics; Biology; Cell differentiation; Cell Differentiation - genetics; Cell Lineage - genetics; Cytokines; Developmental biology; Diabetes; Diabetes mellitus; Embryo cells; Embryogenesis; Embryonic development; Embryonic stem cells; Epigenetics; Gastroenterology; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Genes; Genomes; Genomics; Glucose Tolerance Test; Humans; Insulin; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Islets of Langerhans - embryology; Islets of Langerhans - metabolism; Kinases; Maturation; Medicine; Metabolic disorders; Mice; MicroRNA; miRNA; Nkx2.2 protein; Pancreas; R&D; Reasoning; Research & development; Rodents; Stat3 protein; Stem cell transplantation; Stem cells; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0056024

We have used a previously unavailable model of pancreatic development, derived in vitro from human embryonic stem cells, to capture a time-course of gene, miRNA and histone modification levels in pancreatic endocrine cells. We investigated whether it is possible to better understand, and hence control, the biological pathways leading to pancreatic endocrine formation by analysing this information and combining it with the available scientific literature to generate models using a casual reasoning approach. We show that the embryonic stem cell differentiation protocol is highly reproducible in producing endocrine precursor cells and generates cells that recapitulate many aspects of human embryonic pancreas development, including maturation into functional endocrine cells when transplanted into recipient animals. The availability of whole genome gene and miRNA expression data from the early stages of human pancreatic development will be of great benefit to those in the fields of developmental biology and diabetes research. Our causal reasoning algorithm suggested the involvement of novel gene networks, such as NEUROG3/E2F1/KDM5B and SOCS3/STAT3/IL-6, in endocrine cell development We experimentally investigated the role of the top-ranked prediction by showing that addition of exogenous IL-6 could affect the expression of the endocrine progenitor genes NEUROG3 and NKX2.2.