Temporal Transcriptome Analysis Reveals Dynamic Gene Expression Patterns Driving β-Cell Maturation.

Autor:	Sanavia T; Department of Medical Sciences, University of Torino, Torino, Italy., Huang C; Vanderbilt Program in Developmental Biology, Department of Cell and Developmental Biology, Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States., Manduchi E; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Xu Y; Vanderbilt Program in Developmental Biology, Department of Cell and Developmental Biology, Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN, United States., Dadi PK; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States., Potter LA; Vanderbilt Program in Developmental Biology, Department of Cell and Developmental Biology, Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN, United States., Jacobson DA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States., Di Camillo B; Department of Information Engineering, University of Padova, Padova, Italy., Magnuson MA; Vanderbilt Program in Developmental Biology, Department of Cell and Developmental Biology, Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States., Stoeckert CJ Jr; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Gu G; Vanderbilt Program in Developmental Biology, Department of Cell and Developmental Biology, Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2021 May 04; Vol. 9, pp. 648791. Date of Electronic Publication: 2021 May 04 (Print Publication: 2021).
DOI:	10.3389/fcell.2021.648791
Abstrakt:	Newly differentiated pancreatic β cells lack proper insulin secretion profiles of mature functional β cells. The global gene expression differences between paired immature and mature β cells have been studied, but the dynamics of transcriptional events, correlating with temporal development of glucose-stimulated insulin secretion (GSIS), remain to be fully defined. This aspect is important to identify which genes and pathways are necessary for β-cell development or for maturation, as defective insulin secretion is linked with diseases such as diabetes. In this study, we assayed through RNA sequencing the global gene expression across six β-cell developmental stages in mice, spanning from β-cell progenitor to mature β cells. A computational pipeline then selected genes differentially expressed with respect to progenitors and clustered them into groups with distinct temporal patterns associated with biological functions and pathways. These patterns were finally correlated with experimental GSIS, calcium influx, and insulin granule formation data. Gene expression temporal profiling revealed the timing of important biological processes across β-cell maturation, such as the deregulation of β-cell developmental pathways and the activation of molecular machineries for vesicle biosynthesis and transport, signal transduction of transmembrane receptors, and glucose-induced Ca 2+ influx, which were established over a week before β-cell maturation completes. In particular, β cells developed robust insulin secretion at high glucose several days after birth, coincident with the establishment of glucose-induced calcium influx. Yet the neonatal β cells displayed high basal insulin secretion, which decreased to the low levels found in mature β cells only a week later. Different genes associated with calcium-mediated processes, whose alterations are linked with insulin resistance and deregulation of glucose homeostasis, showed increased expression across β-cell stages, in accordance with the temporal acquisition of proper GSIS. Our temporal gene expression pattern analysis provided a comprehensive database of the underlying molecular components and biological mechanisms driving β-cell maturation at different temporal stages, which are fundamental for better control of the in vitro production of functional β cells from human embryonic stem/induced pluripotent cell for transplantation-based type 1 diabetes therapy. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Sanavia, Huang, Manduchi, Xu, Dadi, Potter, Jacobson, Di Camillo, Magnuson, Stoeckert and Gu.)
Databáze:	MEDLINE
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