Abstract
The pancreas develops due to the function of many interconnected transcription factors and the regulation provided by them. Among the elements that regulate transcription are epigenetic factors, DNA methylation, histone modifications, and noncoding RNAs. Some of these factors regulate the differentiation of endocrine and exocrine tissue, cell fate determination into the distinct types of the endocrine cells (especially alpha and beta), and the maintenance of cell identity. We herein summarize the epigenetic mechanisms that occur during the normal development of the pancreas and also during negative programming due to the effects of some adverse environmental factors in the uterus such as unbalanced maternal nutrition. All the current data come from animal models because of the ability to control variables, the availability of organisms, and the relatively short life cycle. By means of specific cases, we present the importance of epigenetic processes in the normal and altered pancreatic development and function.
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Abbreviations
- Afp:
-
Alpha fetoprotein gene
- Alb:
-
Albumin gene
- ARX:
-
Aristaless related homeobox
- BETA2/NEUROD:
-
Neurogenic differentiation
- CREB:
-
cAMP-response element binding protein
- DNA:
-
Deoxyribonucleic acid
- Ezh2:
-
Enhancer of zeste 2 polycomb repressive complex 2 subunit
- FOXA2:
-
Forkhead box A2
- GK:
-
Glucokinase
- GLPR1:
-
Glucagon-like peptide receptor 1
- GLUT2:
-
Glucose transporter 2
- GSIS:
-
Glucose-stimulated insulin secretion
- HDAC1:
-
Histone deacetylase 1
- HNF:
-
Hepatocyte nuclear factor
- H3K27me3:
-
Trimethylation of lysine 27 at histone 3
- H3K9K14ac:
-
Acetylation of lysine 9 and 14 at histone 3
- IA2:
-
PTPRN, protein tyrosine phosphatase, receptor type N
- IGF:
-
Insulin-like growth factor
- IR:
-
Insulin receptor
- IRS:
-
Insulin receptor substrate
- ISL1:
-
Islet transcription factor 1
- IUGR:
-
Intrauterine growth restriction
- KATP channels:
-
ATP-regulated potassium channels
- MAF:
-
Musculoaponeurotic fibrosarcoma transcription factor
- MECP2:
-
Methyl CpG binding protein 2
- miRNA:
-
MicroRNA
- miR-375:
-
MicroRNA 375
- mTOR:
-
Mechanistic target of rapamycin
- NGN3:
-
Neurogenin 3
- NKX:
-
Homeobox protein NK
- PAX4–6:
-
Paired box 4–6
- PDK1:
-
Pyruvatedehydrogenase kinase 1
- PDX1:
-
Pancreatic and duodenal homeobox 1
- PI3K:
-
Phosphatidylinositol-4, 5-bisphosphate 3-kinase
- PPARGC1A:
-
Peroxisome proliferator activated receptor gamma coactivator-1 alpha
- PPY:
-
Pancreatic polypeptide
- PRMT6:
-
Protein arginine methyltransferase 6
- RNA:
-
Ribonucleic acid
- Sin3A:
-
SIN3 transcription regulator family member A
- SS:
-
Somatostatin
- Ttr:
-
Transthyretin gene
- T2D:
-
Type 2 diabetes
- USF1:
-
Upstream transcription factor 1
References
Abuzgaia AM, Hardy DB, Arany E (2015) Regulation of postnatal pancreatic Pdx1 and downstream target genes after gestational exposure to protein restriction in rats. Reproduction 149:293–303. doi:10.1530/REP-14-0245
Alejandro EU, Gregg B, Wallen T et al (2014) Maternal diet-induced microRNAs and mTOR underlie β cell dysfunction in offspring. J Clin Invest 124:4395–4410. doi:10.1172/JCI74237
Arnes L, Sussel L (2015) Epigenetic modifications and long non-coding RNAs influence pancreas development and function. Trends Genet 31:290–299. doi:10.1016/j.tig.2015.02.008
Benitez CM, Goodyer WR, Kim SK (2012) Deconstructing pancreas developmental biology. Cold Spring Harb Perspect Biol 4:pii: a012401. doi:10.1101/cshperspect
Burgio E, Lopomo A, Migliore L (2015) Obesity and diabetes: from genetics to epigenetics. Mol Biol Rep 42:799–818. doi:10.1007/s11033-014-3751-z
Cerf ME, Chapman CS, Louw J (2012) High-fat programming of hyperglycemia, hyperinsulinemia, insulin resistance, hyperleptinemia, and altered islet architecture in 3-month-old wistar rats. ISRN Endocrinol 2012:627270. doi:10.5402/2012/627270
Choi J, Li C, McDonald TJ et al (2011) Emergence of insulin resistance in juvenile baboon offspring of mothers exposed to moderate maternal nutrient reduction. Am J Physiol Regul Integr Comp Physiol 301:R757–R762. doi:10.1152/ajpregu.00051.2011
Daniel ZC, Akyol A, McMullen S et al (2014) Exposure of neonatal rats to maternal cafeteria feeding during suckling alters hepatic gene expression and DNA methylation in the insulin signalling pathway. Genes Nutr 9:365. doi:10.1007/s12263-013-0365-3
Dahri S, Snoeck A, Reusens-Billen B, Remacle C, Hoet JJ (1991) Islet function in offspring of mothers on low-protein diet during gestation. Diabetes 40(Suppl 2):115–120
Dhawan S, Georgia S, Tschen SI et al (2011) Pancreatic β cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell 20:419–429. doi:10.1016/j.devcel.2011.03.012
Dumortier O, Blondeau B, Duvillié B et al (2007) Different mechanisms operating during different critical time-windows reduce rat fetal beta cell mass due to a maternal low-protein or low-energy diet. Diabetologia 50:2495–2503. doi:10.1007/s00125-007-0811-0
Dumortier O, Hinault C, Gautier N et al (2014) Maternal protein restriction leads to pancreatic failure in offspring: role of misexpressed microRNA-375. Diabetes 63:3416–3427. doi:10.2337/db13-1431
Duque-Guimarães DE, Ozanne SE (2013) Nutritional programming of insulin resistance: causes and consequences. Trends Endocrinol Metab 24:525–535. doi:10.1016/j.tem.2013.05.006
Ford SP, Zhang L, Zhu M et al (2009) Maternal obesity accelerates fetal pancreatic beta-cell but not alpha-cell development in sheep: prenatal consequences. Am J Physiol Regul Integr Comp Physiol 297:R835–R843. doi:10.1152/ajpregu.00072.2009
Garofano A, Czernichow P, Bréant B (1998) Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat. Diabetologia 41:1114–1120. doi:10.1007/s001250051038
Gittes GK (2009) Developmental biology of the pancreas: a comprehensive review. Dev Biol 326:4–35. doi:10.1016/j.ydbio.2008.10.024
Lagos-Quintana M, Rauhut R, Lendeckel W et al (2001) Identification of novel genes coding for small expressed RNAs. Science 294:853–858. doi:10.1126/science.1064921
Liu HW, Mahmood S, Srinivasan M et al (2013) Developmental programming in skeletal muscle in response to overnourishment in the immediate postnatal life in rats. J Nutr Biochem 24:1859–1869. doi:10.1016/j.jnutbio.2013.05.002
Morimoto S, Sosa TC, Calzada L et al (2012a) Developmental programming of aging of isolated pancreatic islet glucose-stimulated insulin secretion in female offspring of mothers fed low-protein diets in pregnancy and/or lactation. J Dev Orig Health Dis 3:483–488. doi:10.1017/S2040174412000463
Morimoto S, Calzada L, Sosa TC, Reyes-Castro LA, Rodriguez-González GL, Morales A, Nathanielsz PW, Zambrano E (2012b) Emergence of ageing-related changes in insulin secretion by pancreatic islets of male rat offspring of mothers fed a low-protein diet. Br J Nutr 107:1562–1565. doi:10.1017/S0007114511004855
Pan FC, Wright C (2011) Pancreas organogenesis: from bud to plexus to gland. Dev Dyn 240:530–565. doi:10.1002/dvdy.22584
Park JH, Stoffers DA, Nicholls RD et al (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 118:2316–2324. doi:10.1172/JCI33655
Remacle C, Dumortier O, Bol V et al (2007) Intrauterine programming of the endocrine pancreas. Diabetes Obes Metab 9(Suppl 2):196–209. doi:10.1111/j.1463-1326.2007.00790.x
Reusens B, Remacle C (2006) Programming of the endocrine pancreas by the early nutritional environment. Int J Biochem Cell Biol 38:913–922. doi:10.1016/j.biocel.2005.10.012
Rhodes P, Craigon J, Gray C et al (2009) Adult-onset obesity reveals prenatal programming of glucose-insulin sensitivity in male sheep nutrient restricted during late gestation. PLoS One 4:e7393. doi:10.1371/journal.pone.0007393
Sandovici I, Smith NH, Nitert MD et al (2011) Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A 108:5449–5454. doi:10.1073/pnas.1019007108
Simmons RA, Templeton LJ, Gertz SJ (2001) Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes 50:2279–2286. doi:10.2337/diabetes.50.10.2279
Slack JM (1995) Developmental biology of the pancreas. Development 121:1569–1580
Sosa-Larios TC, Cerbón MA, Morimoto S (2015) Epigenetic alterations caused by nutritional stress during fetal programming of the endocrine pancreas. Arch Med Res 46:93–100. doi:10.1016/j.arcmed.2015.01.005
Spaeth JM, Walker EM, Stein R (2016) Impact of Pdx1-associated chromatin modifiers on islet β-cells. Diabetes Obes Metab 1:123–127. doi:10.1111/dom.12730
Theys N, Bouckenooghe T, Ahn MT, Remacle C, Reusens B (2009) Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat. Am J Physiol Regul Integr Comp Physiol 297:R1516–R1525. doi:10.1152/ajpregu.00280.2009
Todd SE, Oliver MH, Jaquiery AL et al (2009) Periconceptional undernutrition of ewes impairs glucose tolerance in their adult offspring. Pediatr Res 65:409–413. doi:10.1203/PDR.0b013e3181975efa
Wang W, Shi Q, Guo T et al (2016) PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations. Mol Cell Endocrinol 15:38–48. doi:10.1016/j.mce.2016.03.019
Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23:5293–5300. doi:10.1128/MCB.23.15.5293-5300
Welker S, Gotz C, Servas C et al (2013) Glucose regulates protein kinase CK2 in pancreatic beta-cells and its interaction with PDX-1. Int J Biochem Cell Biol 5:2786e2795. doi:10.1016/j.biocel.2013.10.002
Xu CR, Cole PA, Meyers DJ et al (2011) Chromatin “prepattern” and histone modifiers in a fate choice for liver and pancreas. Science 332:963–966. doi:10.1126/science.1202845
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Ortega-Márquez, A.L., Morales-Miranda, A., Morimoto, S. (2017). Impact of Epigenetic Mechanisms on the Regulation of Gene Expression During Intrauterine Programming of the Endocrine Pancreas. In: Patel, V., Preedy, V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-31143-2_69-1
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DOI: https://doi.org/10.1007/978-3-319-31143-2_69-1
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