Regulatory Roles of PARP-1 and Lipids in Epigenetic Mechanisms

  • Maria Rosaria Faraone-MennellaEmail author
  • Annalisa Masi
  • Carla FerreriEmail author
Reference work entry


Epigenetic modifications, reversibly controlling gene expression, are crucial for interpreting the genome under the influence of physiological factors. The basic processes (DNA methylation and histone modification, DNA accessibility, and chromatin structure) which characterize epigenetics are regulated by an orchestrated series of events. The spectrum of these events is becoming wider and wider, increasing the complexity of the interplay between the basic processes and the multiple side mechanisms responsive to environmental stimuli. The “histone code hypothesis” suggests that combinations of different histone modifications may regulate chromatin structure and transcriptional activity. Among these modifications, a crucial role is played by poly(ADP-ribosyl)ation, the reaction catalyzed by poly(ADP-ribose)polymerase-1 widely recognized as a “genome guardian” for driving the repair of damaged DNA. Increasing evidence indicates also that alterations in membrane phospholipid composition and lipid metabolism may play a role in epigenetics. Moreover, a “lipid code” has been proposed since in the nucleus a lipid fraction is present that seems tightly bound to DNA.

This review will analyze these topics and their possible interplay in epigenetic regulation and discuss the relative role of nutritional and environmental challenges.


DNA damage Diet Epigenetics Fatty acids Histone modification Lipidation Lipidomic Lipid rafts Poly(ADP-ribose) Poly(ADP-ribose)polymerase 

List of Abbreviations




Adenosine diphosphate ribose


5′-Adenosine monophosphate-activated protein kinase




Docosahexaenoic acid


Eicosapentaenoic acid


Estrogen receptor


Fatty acid synthase


Forkhead box protein O1


Histone deacetylase




Michigan cancer foundation-7


Mitochondrial DNA


Mammalian target of rapamycin


Nicotinamide adenine dinucleotide


Noncoding RNA


Nuclear factor-κB






Protein kinase C ζ


Peroxisome proliferator-activating receptor


Polyunsaturated fatty acid


Rapidly accelerated fibrosarcoma


Reactive oxygen species


Sirtuin 1


Sterol regulatory element-binding protein


Signal transducer and activator of transcription 3


  1. Albi E, Viola Magni MP (2004) The role of intranuclear lipids. Biol Cell 96(8):657–667CrossRefGoogle Scholar
  2. Altmeyer M, Hottiger MO (2009) Poly(ADP-ribose) polymerase 1 at the crossroad of metabolic stress and inflammation in aging. Aging (Albany NY) 1(5):458–469Google Scholar
  3. Baenke F, Peck B, Miess H, Schulze A (2013) Hooked on fat: the role of lipid synthesis in cancer metabolism and tumor development. Dis Model Mech 6(6):1353–1363CrossRefGoogle Scholar
  4. Bai P, Cantò C (2012) The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell Metab 16(3):290–295CrossRefGoogle Scholar
  5. Balla T (2016) Cell biology: lipid code for membrane recycling. Nature 529(7586):292–293CrossRefGoogle Scholar
  6. Beneke S (2012) Regulation of chromatin structure by poly(ADP-ribosyl)ation. Front Genet 3:169CrossRefGoogle Scholar
  7. Beneke S, Bürkle A (2007) Poly(ADP-ribosyl)ation in mammalian aging. Nucl Ac Res 35(22):7456–7465CrossRefGoogle Scholar
  8. Bianchi AR, Ferreri C, Ruggiero S, Deplano S et al (2016) Automodification of PARP and fatty acid-based membrane lipidome as a promising integrated biomarker panel in molecular medicine. Biomark Med 10(3):229–242CrossRefGoogle Scholar
  9. Bolognesi A, Chatgilialoglu A, Polito L, Ferreri C (2013) Membrane lipidome reorganization correlates with the fate of neuroblastoma cells supplemented with fatty acids. PLoS One 8(2):e55537CrossRefGoogle Scholar
  10. Caiafa P (2000–2013) PARP and epigenetic regulation. In: Madame Curie bioscience database. Landes Bioscience, AustinGoogle Scholar
  11. Calder PC (2001) Polyunsaturated fatty acids, inflammation, and immunity. Lipids 36:1007–1024CrossRefGoogle Scholar
  12. Cantó C, Sauve AA, Bai P (2013) Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. Mol Asp Med 34(6).
  13. Caron A, Richard D, Laplante M (2015) The roles of mTOR complexes in lipid metabolism. Annu Rev Nutr 35:321–348CrossRefGoogle Scholar
  14. Choi SW, Friso S (2010) Epigenetics: a new bridge between nutrition and health. Adv Nutr 1:8–16CrossRefGoogle Scholar
  15. Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz A et al (2014) Acetate dependence of tumors. Cell 159(7):1591–1602CrossRefGoogle Scholar
  16. Davie JR (2003) Inhibition of histone deacetylase activity by Butyrate. J Nutr 133(7):2485S–2493SCrossRefGoogle Scholar
  17. Deckelbaum RJ, Worgall TS, Seo T (2006) n-3 fatty acids and gene expression. Am J Clin Nutr 83:1520S–1525SCrossRefGoogle Scholar
  18. Erener S, Hesse M, Kostadinova R, Hottiger MO (2012) PARP1 controls adipogenic gene expression and adipocyte function. Mol Endocrinol 26(1):79–86CrossRefGoogle Scholar
  19. Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free RadicBiol Med 11:81–128CrossRefGoogle Scholar
  20. Faraone Mennella MR (2011) Mammalian spermatogenesis, DNA repair, Poly(ADP-ribose) turnover: the state of the art. In: Storici F (ed) On the pathways to fixing DNA damage and errors. InTech, pp 235–254.
  21. Faraone-Mennella MR (2015) A new facet of ADP-ribosylation reactions: SIRTs and PARPs interplay. Front Biosc (Landmark Edition) 20:458–473CrossRefGoogle Scholar
  22. Ferreri C, Chatgilialoglu C (2012) Role of fatty acid-based functional lipidomics in the development of molecular diagnostic tools. Expert Rev Mol Diagn 12:767–780CrossRefGoogle Scholar
  23. Ferreri C, Chatgilialoglu C (2015) Membrane lipidomics for personalized health. Wiley, New YorkCrossRefGoogle Scholar
  24. Ferreri C, Masi A, Sansone A, Giacometti G, Larocca AV, Menounou G, Scanferlato R, Tortorella S, Rota D, Conti M, Deplano S, Louka M, Maranini AR, Salat A, Sunda V, Chatgilialoglu C (2017) Fatty acids in membranes as homeostatic, metabolic and nutritional biomarkers: recent advancements in analytics and diagnostics. Diagnostics 7:1. Scholar
  25. Hottiger MO (2015) Nuclear ADP-Ribosylation and its role in chromatin plasticity, cell differentiation, and epigenetics. Annu Rev Biochem 84:227–263CrossRefGoogle Scholar
  26. Kaliman P, Parrizas M (2011) Obesity and systemic inflammation: insights into epigenetic mechanisms. In: Croniger C (ed) Role of the adipocyte in development of type 2 diabetes. InTech, pp 65–88. ISBN: 978-953-307-598-3Google Scholar
  27. Kassan M, Choi SK, Galan M, Bishop A, Umezawa K, Trebak M et al (2013) Enhanced NFkappaB activity impairs vascular function through PARP-1, SP-1 and COX2-dependent mechanisms in type 2 diabetes. Diabetes 62(6):2078–2087CrossRefGoogle Scholar
  28. Keating ST, El-Osta A (2015) Epigenetics and metabolism. Circ Res 116:715–736CrossRefGoogle Scholar
  29. Kiss B, Szántó M, Szklenár M, Brunyánszki A, Marosvölgyi T, Sárosi E et al (2015) Poly(ADP-ribose) polymerase-1 ablation alters eicosanoid and docosanoid signaling and metabolism in a murine model of contact hypersensitivity. Mol Med Rep 11(4):2861–2867CrossRefGoogle Scholar
  30. Kristjuhan A, Walker J, Suka N, Grunstein M et al (2002) Transcriptional inhibition of genes with severe histone H3 hypoacetylation in the coding region. Mol Cell 10(4):925–933CrossRefGoogle Scholar
  31. Lands WE (1958) Metabolism of glycerolipides; a comparison of lecithin and triglyceride synthesis. J Biol Chem 231:883–888PubMedGoogle Scholar
  32. Lapucci A, Pittelli M, Rapizzi E, Felici R, Moroni F, Chiarugi A (2011) PARP1 is a nuclear epigenetic regulator of mitochondrial DNA repair and transcription. Mol Pharmacol 79:932–940CrossRefGoogle Scholar
  33. Latham T, Mackay L, Sproul D, Karim M, Culley J et al (2012) Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression. Nucl Ac Res 40(11):4794–4803CrossRefGoogle Scholar
  34. Lazzarini A, Macchiarulo A, Floridi A, Coletti A et al (2015) Very-long-chain fatty acid sphingomyelin in nuclear lipid microdomains of hepatocytes and hepatoma cells: can the exchange from C24:0 to C16:0 affect signal proteins and vitamin D receptor? Mol Biol Cell 26(13):2418–2425CrossRefGoogle Scholar
  35. Lichtenberg D, Goñi FM, Heerklotz H (2005) Detergent-resistant membranes should not be identified with membrane rafts. Trends Biochem Sci 30(8):430–436CrossRefGoogle Scholar
  36. Lopez S, Bermudez B, Montserrat-de la Paz S, Jaramillo S et al (2014) Membrane composition and dynamics: a target of bioactive virgin olive oil constituents. Biochim Biophys Acta Biomembr 1838(6):1638–1656. ISSN 0005-2736CrossRefGoogle Scholar
  37. Luo X, Kraus WL (2012) On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev 26(5):417–432CrossRefGoogle Scholar
  38. Maraldi NM, Capitani S, Caramelli E, Cocco L et al (1984) Conformational changes of nuclear chromatin related to phospholipid induced modifications of the template availability. Adv Enzym Regul 22:447–464CrossRefGoogle Scholar
  39. Mouritsen OG (2005) Life – as a matter of fat. The emerging science of lipidomics. The frontiers collection. Springer, BerlinGoogle Scholar
  40. Ohanna M, Giuliano S, Bonet C, Imbert V et al (2011) Senescent cells develop a PARP-1 and nuclear factor-κB-associated secretome (PNAS). Genes Dev 25(12):1245–1261CrossRefGoogle Scholar
  41. Pégorier JP, Le May C, Girard J (2004) Control of gene expression by fatty acids. J Nutr 134:2444S–2449SCrossRefGoogle Scholar
  42. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tscho MH (2008) Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A 105(28):9793–9798CrossRefGoogle Scholar
  43. Pirrotta V (2003) Transcription. Puffing with PARP. Science 299(5606):528–529CrossRefGoogle Scholar
  44. Raghavan V, Vijayaraghavalu S, Peetla C, Yamada M et al (2015) Sustained epigenetic drug delivery depletes cholesterol-sphingomyelin rafts from resistant breast cancer cells, influencing biophysical characteristics of membrane lipids. Langmuir 31(42):11564–11573CrossRefGoogle Scholar
  45. Rodríguez-Vargas JM, Ruiz-Magaña MJ, Ruiz-Ruiz C, Majuelos-Melguizo J et al (2012 Jul) ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy. Cell Res 22(7):1181–1198CrossRefGoogle Scholar
  46. Sadli N, Ahmed N, Ackland ML, Sinclair A et al (2011) Effect of zinc and DHA on expression levels and post-translational modifications of histones H3 and H4 in human neuronal cells. In: Dr Chang RCC (ed) Neurodegenerative diseases – processes, prevention, protection and monitoring. InTech, Rijeka, pp 141–164Google Scholar
  47. Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–528CrossRefGoogle Scholar
  48. Ventura R, Mordec K, Waszczuk J, Wang Z et al (2015) Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming Gene expression. EBio Med 2(8):808–824Google Scholar
  49. Virág L, Szabó C (2002) The therapeutic potential of PARP inhibitors. Pharmacol Rev 54:375–429CrossRefGoogle Scholar
  50. Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23(15):5293–5300CrossRefGoogle Scholar
  51. Wu X, Dong Z, Wang CJ, Barlow LJ et al (2016) FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1. Proc Natl Acad Sci U S A 113(45):E6965–EE973CrossRefGoogle Scholar
  52. Xu S, Bai P, Little J, Liu P (2014) PARP1 in atherosclerosis: from molecular mechanisms to therapeutic implications. Med Res Rev 34(3):644–675CrossRefGoogle Scholar
  53. Zerfaoui M, Errami Y, Naura AS, Suzuki Y et al (2010) PARP1 is a determining factor in Crm1-mediated nuclear export and retention of p65 NF-kappa B upon TLR4 stimulation. J Immunol 185(3):1894–1902CrossRefGoogle Scholar
  54. Zhao S, Xu W, Jiang W, Yu W et al (2010) Regulation of cellular metabolism by protein lysine acetylation. Science 327(5968):1000–1004CrossRefGoogle Scholar
  55. Zhdanov R, Schirmer EC, Venkatasubramani AV, Kerr ARV et al (2015) Lipids contribute to epigenetic control via chromatin structure and functions. Sci Open Res.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of BiologyUniversity of Naples “Federico II”NaplesItaly
  2. 2.Institute of Organic Synthesis and Photoreactivity (ISOF), CNRBolognaItaly

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