Epigenetics, cell cycle and stem cell metabolism. Formation of insulin-producing cells





stem cells, epigenetic modifications, cell cycle, metabolism, calcium ions, insulin-producing cells


Stem cell (SC) differentiation requires a series of chromatin rearrangements to establish cell identity. Posttranslational modifications of histones usually regulate the dynamics of hete­rochromatin. Histones are subjected to various modifications, such as acetylation, methylation, phosphorylation and ubiquinination, and thus contribute to regulation of chromatin status and trans­criptional activity. The chemically stable pattern of methylated histones promotes cellular memory relative to external stimuli, maintaining transcription levels of adaptive genes even after elimi­nation of environmental signals. Chromatin mo­difications play an important role in the maturation of pancreatic islet cells, the establishment of a secretion pattern that stimulates the regu­lation of insulin secretion. MicroRNAs, a class of endo­genous small noncoding RNAs in eukaryotes, are important regulators of gene expression at the level of posttranscriptional mecha­nisms. MicroRNAs regulate insulin secretion, pancreatic deve­lopment, and β-cell differentiation. Pluripotent SCs are characterized by a high rate of proliferation, the ability to self-repair and the potential for differentiation in different cell types. This rapid proliferation is due to a modified cell cycle that allows cells to rapidly transition from DNA synthesis to cell division by reducing the time of gap (G1 and G2) phases. The canonical WNT/β-ca­tenin signaling pathway is characterized as a major driver of cell growth and proliferation. At G1, WNT signaling induces a transition to the S-phase. Compared to their somatic counterparts, pluripotent SCs exhibit a high rate of glycolysis similar to aerobic glycolysis in cancer cells, a phenomenon known as the Warburg effect, which is important for maintaining SC properties. In stem cells, the extracellular influx of Ca2+ into the cytoplasm is mediated mainly by depot-controlled Ca2+ channels. Extracellular cal­cium has been shown to promote SC proliferation and thus may be involved in transplant therapy.


Download data is not yet available.


Krentz NAJ, Gloyn AL. Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics. Nat Rev Endocrinol. 2020 Apr;16(4):202-212. doi: 10.1038/s41574-020-0325-0.

Kampmann M. CRISPR-based functional genomics for neurological disease. Nat Rev Neurol. 2020;16(9):465-80. doi: 10.1038/s41582-020-0373-z.

Astro V, Adamo A. Epigenetic Control of Endocrine Pancreas Differentiation in vitro: Current Knowledge and Future Perspectives. Front Cell Dev Biol. 2018;6:141. doi: 10.3389/fcell.2018.00141.

Nicetto D, Donahue G, Jain T, et al. H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification. Science. 2019;363(6424):294-7. doi: 10.1126/science.aau0583.

Thienpont B, Aronsen JM, Robinson EL, et al. The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. J Clin Invest. 2017;127(1):335-48. doi: 10.1172/JCI88353.

Strom AR, Emelyanov AV, Mir M, Fyodorov DV, Darzacq X, Karpen GH. Phase separation drives heterochromatin domain formation. Nature. 2017 Jul 13;547(7662):241-245. doi: 10.1038/nature22989.

Ninova M, Fejes Tóth K, Aravin AA. The control of gene expression and cell identity by H3K9 trimethylation. Development. 2019;146(19):dev181180. doi: 10.1242/dev.181180.

Lu TT, Heyne S, Dror E, Casas E, Leonhardt L, Boenke T, et al. The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes. Cell Metab. 2018;27(6):1294-308.e7. doi: 10.1016/j.cmet.2018.04.013.

Lee DH, Kim GW, Jeon YH, Yoo J, Lee SW, Kwon SH. Advances in histone demethylase KDM4 as cancer therapeutic targets. FASEB J. 2020;34(3):3461-84. doi: 10.1096/fj.201902584R.

Rosales W, Lizcano F. The Histone Demethylase JMJD2A Modulates the Induction of Hypertrophy Markers in iPSC-Derived Cardiomyocytes. Front Genet. 2018;9:14. doi: 10.3389/fgene.2018.00014.

Arroyave F, Montaño D, Lizcano F. Diabetes Mellitus Is a Chronic Disease that Can Benefit from Therapy with Induced Pluripotent Stem Cells. Int J Mol Sci. 2020;21(22):8685. doi: 10.3390/ijms21228685.

Zhang T, Huang K, Zhu Y, et al. Vitamin C-dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition. J Biol Chem. 2019;294(37):13657-13670. doi: 10.1074/jbc.RA119.009757.

Coskun E, Ercin M, Gezginci-Oktayoglu S. The Role of Epigenetic Regulation and Pluripotency-Related MicroRNAs in Differentiation of Pancreatic Stem Cells to Beta Cells. J Cell Biochem. 2018;119(1):455-467. doi: 10.1002/jcb.26203.

Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-76. doi: 10.1016/j.cell.2006.07.024.

Liu X, Ouyang JF, Rossello FJ, et al. Reprogramming roadmap reveals route to human induced trophoblast stem cells. Nature. 2020 Oct;586(7827):101-107. doi: 10.1038/s41586-020-2734-6.

Wang Y, Bi Y, Gao S. Epigenetic regulation of somatic cell reprogramming. Curr. Opin. Genet. Dev. 2017;46:156–163. doi: 10.1016/j.gde.2017. 07.002.

Di Stefano M, Stadhouders R, Farabella I, et al. Transcriptional activation during cell reprogramming correlates with the formation of 3D open chromatin hubs. Nat. Commun. 2020;11(1):2564. doi: 10.1038/s41467-020-16396-1.

Lu L, Liu X, Huang WK, et al. Robust Hi-C Maps of Enhancer-Promoter Interactions Reveal the Function of Non-coding Genome in Neural Development and Diseases. Mol Cell. 2020 Aug 6;79(3):521-534.e15. doi: 10.1016/j.molcel.2020.06.007.

Stadhouders R, Vidal E, Serra F, et al. Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming. Nat Genet. 2018 Feb;50(2):238-249. doi: 10.1038/s41588-017-0030-7.

Li D, Liu J, Yang X, et al. Chromatin Accessibility Dynamics during iPSC Reprogramming. Cell Stem Cell. 2017 Dec 7;21(6):819-833.e6. doi: 10.1016/j.stem.2017.10.012.

Sun L, Fu X, Ma G, Hutchins AP. Chromatin and Epigenetic Rearrangements in Embryonic Stem Cell Fate Transitions. Front Cell Dev Biol. 2021 Feb 18;9:637309. doi: 10.3389/fcell.2021.637309.

Chen J, Guo L, Zhang L, et al. Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet. 2013 Dec;45(12):1504-9. doi: 10.1038/ng.2807.

Arabacı DH, Terzioğlu G, Bayırbaşı B, Önder TT. Going up the hill: chromatin-based barriers to epigenetic reprogramming. FEBS J. 2021 Aug;288(16):4798-4811. doi: 10.1111/febs.15628.

Chen J, Liu H, Liu J, et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat Genet. 2013 Jan;45(1):34-42. doi: 10.1038/ng.2491.

Miles DC, de Vries NA, Gisler S, et al. TRIM28 is an Epigenetic Barrier to Induced Pluripotent Stem Cell Reprogramming. Stem Cells. 2017 Jan;35(1):147-157. doi: 10.1002/stem.2453.

Klimczak M, Czerwińska P, Mazurek S, et al. TRIM28 epigenetic corepressor is indispensable for stable induced pluripotent stem cell formation. Stem Cell Res. 2017 Aug;23:163-172. doi: 10.1016/j.scr.2017.07.012.

Chronis C, Fiziev P, Papp B, et al. Cooperative Binding of Transcription Factors Orchestrates Reprogramming. Cell. 2017 Jan 26;168(3):442-459.e20. doi: 10.1016/j.cell.2016.12.016.

Zhuang Q, Li W, Benda C, et al. NCoR/SMRT co-repressors cooperate with c-MYC to create an epigenetic barrier to somatic cell reprogramming. Nat Cell Biol. 2018 Apr;20(4):400-412. doi: 10.1038/s41556-018-0047-x.

Huang Y, Zhang H, Wang L, et al. JMJD3 acts in tandem with KLF4 to facilitate reprogramming to pluripotency. Nat Commun. 2020 Oct 8;11(1):5061. doi: 10.1038/s41467-020-18900-z.

Rao RA, Dhele N, Cheemadan S, et al. Ezh2 mediated H3K27me3 activity facilitates somatic transition during human pluripotent reprogramming. Sci Rep. 2015 Feb 4;5:8229. doi: 10.1038/srep08229.

Li H, Lai P, Jia J, et al. RNA Helicase DDX5 Inhibits Reprogramming to Pluripotency by miRNA-Based Repression of RYBP and its PRC1-Dependent and -Independent Functions. Cell Stem Cell. 2017 Apr 6;20(4):462-477.e6. doi: 10.1016/j.stem.2016.12.002.

Sun ZY, Yu TY, Jiang FX, Wang W. Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes. World J Stem Cells. 2021 Mar 26;13(3):193-207. doi: 10.4252/wjsc.v13.i3.193.

Boward B, Wu T, Dalton S. Concise Review: Control of Cell Fate through Cell Cycle and Pluripotency Networks. Stem Cells. 2016;34(6):1427-36. doi: 10.1002/stem.2345.

Rasmussen ML, Ortolano NA, Romero-Morales AI, Gama V. Wnt Signaling and It’s Impact on Mitochondrial and Cell Cycle Dynamics in Pluripotent Stem Cells. Genes (Basel). 2018;9(2):109. doi: 10.3390/genes9020109.

Zaveri L, Dhawan J. Cycling to Meet Fate: Connecting Pluripotency to the Cell Cycle. Front Cell Dev Biol. 2018;6:57. doi: 10.3389/fcell.2018.00057.

Kolupaeva V, Janssens V. PP1 and PP2A phosphatases-cooperating partners in modulating retinoblastoma protein activation. FEBS J. 2013;280(2):627-43. doi: 10.1111/j.1742-4658.2012.08511.x.

Bertoli C, Skotheim JM, de Bruin RA. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol. 2013;14(8):518-28. doi: 10.1038/nrm3629.

Soufi A, Dalton S. Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming. Development. 2016;143(23):4301-4311. doi: 10.1242/dev.142075.

Ter Huurne M, Chappell J, Dalton S, Stunnenberg HG. Distinct Cell-Cycle Control in Two Different States of Mouse Pluripotency. Cell Stem Cell. 2017;21(4):449-55.e4. doi: 10.1016/j.stem.2017.09.004.

Pauklin S, Vallier L. The cell-cycle state of stem cells determines cell fate propensity. Cell. 2013;155(1):135-47. doi: 10.1016/j.cell.2013.08.031. Erratum in: Cell. 2014;156(6):1338.

Pauklin S, Madrigal P, Bertero A, Vallier L. Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D. Genes Dev. 2016;30(4):421-433. doi: 10.1101/gad.271452.115.

Liu L, Michowski W, Inuzuka H, et al. G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells. Nat Cell Biol. 2017;19(3):177-188. doi: 10.1038/ncb3474.

Roccio M, Schmitter D, Knobloch M, Okawa Y, Sage D, Lutolf MP. Predicting stem cell fate changes by differential cell cycle progression patterns. Development. 2013;140(2):459-470. doi: 10.1242/dev.086215.

Ponti G, Obernier K, Guinto C, Jose L, Bonfanti L, Alvarez-Buylla A. Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice. Proc Natl Acad Sci U S A. 2013;110(11):E1045-54. doi: 10.1073/pnas.1219563110.

Pauklin S, Vallier L. The cell-cycle state of stem cells determines cell fate propensity. Cell. 2013;155(1):135-47. doi: 10.1016/j.cell.2013.08.031.

Davidson G. The cell cycle and Wnt. Cell Cycle. 2010 May;9(9):1667-8. doi: 10.4161/cc.9.9.11595.

De Jaime-Soguero A, Aulicino F, Ertaylan G, et al. Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. PLoS Genet. 2017;13(3):e1006682. doi: 10.1371/journal.pgen.1006682.

Kim KP, Han DW, Kim J, Schöler HR. Biological importance of OCT transcription factors in reprogramming and development. Exp Mol Med. 2021;53(6):1018-1028. doi: 10.1038/s12276-021-00637-4.

Ebrahimi A, Sevinç K, Gürhan Sevinç G, et al. Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming. Nat Chem Biol. 2019 May;15(5):519-528. doi: 10.1038/s41589-019-0264-z.

Kim KP, Choi J, Yoon J, et al. Permissive epigenomes endow reprogramming competence to transcriptional regulators. Nat Chem Biol. 2021 Jan;17(1):47-56. doi: 10.1038/s41589-020-0618-6.

Kim KP, Wu Y, Yoon J, et al. Reprogramming competence of OCT factors is determined by transactivation domains. Sci Adv. 2020;6(36):eaaz7364. doi: 10.1126/sciadv.aaz7364.

Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotency in human somatic cells via a transient state resembling primitive streak-like mesendoderm. Nat Commun. 2014;5:3678. doi: 10.1038/ncomms4678.

Ishida T, Nakao S, Ueyama T, Harada Y, Kawamura T. Metabolic remodeling during somatic cell reprogramming to induced pluripotent stem cells: involvement of hypoxia-inducible factor 1. Inflamm Regen. 2020 May 12;40:8. doi: 10.1186/s41232-020-00117-8.

Ahamad N, Singh BB. Calcium channels and their role in regenerative medicine. World J Stem Cells. 2021;13(4):260-280. doi: 10.4252/wjsc.v13.i4.260.

Uzieliene I, Bernotas P, Mobasheri A, Bernotiene E. The Role of Physical Stimuli on Calcium Channels in Chondrogenic Differentiation of Mesenchymal Stem Cells. Int J Mol Sci. 2018 Oct 1;19(10):2998. doi: 10.3390/ijms19102998.

Uzieliene I, Bernotas P, Mobasheri A, Bernotiene E. The Role of Physical Stimuli on Calcium Channels in Chondrogenic Differentiation of Mesenchymal Stem Cells. Int J Mol Sci. 2018;19(10):2998. doi: 10.3390/ijms19102998.

Hao B, Webb SE, Miller AL, Yue J. The role of Ca(2+) signaling on the self-renewal and neural differentiation of embryonic stem cells (ESCs). Cell Calcium. 2016;59(2-3):67-74. doi: 10.1016/j.ceca.2016.01.004.

Davenport B, Li Y, Heizer JW, Schmitz C, Perraud AL. Signature Channels of Excitability no More: L-Type Channels in Immune Cells. Front Immunol. 2015;6:375. doi: 10.3389/fimmu.2015.00375.

Tan YZ, Fei DD, He XN, et al. L-type voltage-gated calcium channels in stem cells and tissue engineering. Cell Prolif. 2019;52(4):e12623. doi: 10.1111/cpr.12623.

Uslu M, Albayrak E, Kocabaş F. Temporal modulation of calcium sensing in hematopoietic stem cells is crucial for proper stem cell expansion and engraftment. J Cell Physiol. 2020;235(12):9644-9666. doi: 10.1002/jcp.29777. 

Lee MN, Hwang HS, Oh SH, et al. Elevated extracellular calcium ions promote proliferation and migration of mesenchymal stem cells via increasing osteopontin expression. Exp Mol Med. 2018;50(11):1-16. doi: 10.1038/s12276-018-0170-6.

Liu MY, Hua WK, Chiou YY, et al. Calcium-dependent methylation by PRMT1 promotes erythroid differentiation through the p38α MAPK pathway. FEBS Lett. 2020;594(2):301-316. doi: 10.1002/1873-3468.13614.

Pchelintseva E, Djamgoz MBA. Mesenchymal stem cell differentiation: Control by calcium-activated potassium channels. J Cell Physiol. 2018;233(5):3755-3768. doi: 10.1002/jcp.26120.  

Jiang LH, Mousawi F, Yang X, Roger S. ATP-induced Ca2+-signalling mechanisms in the regulation of mesenchymal stem cell migration. Cell Mol Life Sci. 2017;74(20):3697-3710. doi: 10.1007/s00018-017-2545-6.

Ahamad N, Sun Y, Nascimento Da Conceicao V, et al. Differential activation of Ca2+ influx channels modulate stem cell potency, their proliferation/viability and tissue regeneration. NPJ Regen Med. 2021;6(1):67. doi: 10.1038/s41536-021-00180-w.

Ahamad N, Sun Y, Singh BB. Increasing cytosolic Ca2+ levels restore cell proliferation and stem cell potency in aged MSCs. Stem Cell Res. 2021;56:102560. doi: 10.1016/j.scr.2021.102560.

Jirawatnotai S, Dalton S, Wattanapanitch M. Role of cyclins and cyclin-dependent kinases in pluripotent stem cells and their potential as a therapeutic target. Semin Cell Dev Biol. 2020;107:63-71. doi: 10.1016/j.semcdb.2020.05.001.



How to Cite

Tronko, M., Pushkarev, V., Kovzun, E., Sokolova, L., & Pushkarev, V. (2022). Epigenetics, cell cycle and stem cell metabolism. Formation of insulin-producing cells. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine), 18(3), 169–179. https://doi.org/10.22141/2224-0721.18.3.2022.1165



Literature Review

Most read articles by the same author(s)

1 2 3 > >>