The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression

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Abstract

Background

Insulin producing beta cell and glucagon producing alpha cells are colocalized in pancreatic islets in an arrangement that facilitates the coordinated release of the two principal hormones that regulate glucose homeostasis and prevent both hypoglycemia and diabetes. However, this intricate organization has also complicated the determination of the cellular source(s) of the expression of genes that are detected in the islet. This reflects a significant gap in our understanding of mouse islet physiology, which reduces the effectiveness by which mice model human islet disease.

Results

To overcome this challenge, we generated a bitransgenic reporter mouse that faithfully labels all beta and alpha cells in mouse islets to enable FACS-based purification and the generation of comprehensive transcriptomes of both populations. This facilitates systematic comparison across thousands of genes between the two major endocrine cell types of the islets of Langerhans whose principal hormones are of cardinal importance for glucose homeostasis. Our data leveraged against similar data for human beta cells reveal a core common beta cell transcriptome of 9900+ genes. Against the backdrop of overall similar beta cell transcriptomes, we describe marked differences in the repertoire of receptors and long non-coding RNAs between mouse and human beta cells.

Conclusions

The comprehensive mouse alpha and beta cell transcriptomes complemented by the comparison of the global (dis)similarities between mouse and human beta cells represent invaluable resources to boost the accuracy by which rodent models offer guidance in finding cures for human diabetes.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-620) contains supplementary material, which is available to authorized users.

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Most cited references 51

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The evolution of lncRNA repertoires and expression patterns in tetrapods.

Anamaria Necsulea, Magali Soumillon, Maria Warnefors … (2014)

Only a very small fraction of long noncoding RNAs (lncRNAs) are well characterized. The evolutionary history of lncRNAs can provide insights into their functionality, but the absence of lncRNA annotations in non-model organisms has precluded comparative analyses. Here we present a large-scale evolutionary study of lncRNA repertoires and expression patterns, in 11 tetrapod species. We identify approximately 11,000 primate-specific lncRNAs and 2,500 highly conserved lncRNAs, including approximately 400 genes that are likely to have originated more than 300 million years ago. We find that lncRNAs, in particular ancient ones, are in general actively regulated and may function predominantly in embryonic development. Most lncRNAs evolve rapidly in terms of sequence and expression levels, but tissue specificities are often conserved. We compared expression patterns of homologous lncRNA and protein-coding families across tetrapods to reconstruct an evolutionarily conserved co-expression network. This network suggests potential functions for lncRNAs in fundamental processes such as spermatogenesis and synaptic transmission, but also in more specific mechanisms such as placenta development through microRNA production.

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Serotonin Regulates Pancreatic β-Cell Mass during Pregnancy

Hail Kim, Yukiko Toyofuku, Francis Lynn … (2010)

During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing β-cells1–3. However, the exact mechanisms by which the lactogenic hormones drive β-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive β-cell proliferation. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in β-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked β-cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gαq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gαi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked β-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking β-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes4.

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Inactivation of specific β cell transcription factors in type 2 diabetes.

Maike Sander, Shuangli Guo, Roland Gregor Stein … (2013)

Type 2 diabetes (T2DM) commonly arises from islet β cell failure and insulin resistance. Here, we examined the sensitivity of key islet-enriched transcription factors to oxidative stress, a condition associated with β cell dysfunction in both type 1 diabetes (T1DM) and T2DM. Hydrogen peroxide treatment of β cell lines induced cytoplasmic translocation of MAFA and NKX6.1. In parallel, the ability of nuclear PDX1 to bind endogenous target gene promoters was also dramatically reduced, whereas the activity of other key β cell transcriptional regulators was unaffected. MAFA levels were reduced, followed by a reduction in NKX6.1 upon development of hyperglycemia in db/db mice, a T2DM model. Transgenic expression of the glutathione peroxidase-1 antioxidant enzyme (GPX1) in db/db islet β cells restored nuclear MAFA, nuclear NKX6.1, and β cell function in vivo. Notably, the selective decrease in MAFA, NKX6.1, and PDX1 expression was found in human T2DM islets. MAFB, a MAFA-related transcription factor expressed in human β cells, was also severely compromised. We propose that MAFA, MAFB, NKX6.1, and PDX1 activity provides a gauge of islet β cell function, with loss of MAFA (and/or MAFB) representing an early indicator of β cell inactivity and the subsequent deficit of more impactful NKX6.1 (and/or PDX1) resulting in overt dysfunction associated with T2DM.

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Author and article information

Contributors

Christopher Benner: cbenner@salk.edu

Talitha van der Meulen: tmeulen@salk.edu

Elena Cacéres: ecaceres@salk.edu

Kristof Tigyi: ktigyi@salk.edu

Cynthia J Donaldson: donaldson@salk.edu

Mark O Huising: mhuising@ucdavis.edu

Journal

Journal ID (nlm-ta): BMC Genomics

Journal ID (iso-abbrev): BMC Genomics

Title: BMC Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2164

Publication date (Electronic): 22 July 2014

Publication date PMC-release: 22 July 2014

Publication date Collection: 2014

Volume: 15

Issue: 1

Electronic Location Identifier: 620

Affiliations

[ ]Razzavi Newman Integrated Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037 USA

[ ]Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037 USA

[ ]Department of Neurobiology, Physiology & Behavior, University of California, One Shields Avenue, 180 Briggs Hall, Davis, CA 95616 USA

Article

Publisher ID: 6324

DOI: 10.1186/1471-2164-15-620

PMC ID: 4124169

PubMed ID: 25051960

SO-VID: 3c3c88b9-854a-4c51-8855-048d720c9618

License:

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 March 2014

Date accepted : 10 July 2014

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: beta cell,alpha cell,pancreatic islet,insulin,glucagon,ucn3,crh,diabetes,lncrna,rna-seq,prolactin receptor,prlr,growth hormone receptor,ghr,ciliary neurotrophic factor receptor,cntfr,islet amyloid polypeptide,iapp,amylin,ets1

Data availability:

ScienceOpen disciplines: Genetics

Keywords: beta cell, alpha cell, pancreatic islet, insulin, glucagon, ucn3, crh, diabetes, lncrna, rna-seq, prolactin receptor, prlr, growth hormone receptor, ghr, ciliary neurotrophic factor receptor, cntfr, islet amyloid polypeptide, iapp, amylin, ets1

The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression

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Abstract

Background

Results

Conclusions

Electronic supplementary material

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RNA drug delivery

Most cited references 51

The evolution of lncRNA repertoires and expression patterns in tetrapods.

Serotonin Regulates Pancreatic β-Cell Mass during Pregnancy

Inactivation of specific β cell transcription factors in type 2 diabetes.

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