Abstract
Even though the majority of knowledge about phospholipids comes from their cytoplasmic functions, in the last decade, it has been shown that nuclear phospholipids and their building blocks, inositol phosphates, have many important roles in the cell nucleus. There are clear connections of phospholipids with the regulation of gene expression and chromatin biology, however, this review focuses on less known functions of nuclear phospholipids in connection with the epigenome regulation. In particular, we highlight the roles of nuclear phospholipids and inositol phosphates that involve histone modifications, such as acetylation or methylation, tightly connected with the cell physiology. This demonstrates the importance of nuclear phospholipids in the regulation of cellular processes, and should encourage further research of nuclear phospholipids and inositol phosphates.
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References
Albi E, Lazzarini R, Viola Magni M (2008) Phosphatidylcholine/sphingomyelin metabolism crosstalk inside the nucleus. Biochem J 1410(2):381–389
Alcázar-Román A, Wente S (2008) Inositol polyphosphates: a new frontier for regulating gene expression. Chromosoma 117(1):1–13. https://doi.org/10.1007/s00412-007-0126-4
Alessenko A, Burlakova E (2002) Functional role of phospholipids in the nuclear events. Bioelectrochemistry 58(1):13–21. https://doi.org/10.1016/S1567-5394(02)00135-4
Alvarez-Venegas R, Sadder M, Hlavacka A, Baluska F, Xia Y, Lu G, Firsov A, Sarath G, Moriyama H, Dubrovsky JG, Avramova Z (2006) The Arabidopsis homolog of trithorax, ATX1, binds phosphatidylinositol 5-phosphate, and the two regulate a common set of target genes. Proc Natl Acad Sci USA 103(15):6049–6054. https://doi.org/10.1073/pnas.0600944103
Bernstein B, Meissner A, Lander E (2007) The mammalian epigenome. Cell 128(4):669–681. https://doi.org/10.1016/j.cell.2007.01.033
Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16(1):6–21. https://doi.org/10.1101/gad.947102
Boronenkov IV, Loijens JC, Umeda M, Anderson RA (1998) Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre-mRNA processing factors. Mol Biol Cell 9(12):3547–3560
Bremer J, Greenberg D (1961) Methyl transferring enzyme system of microsomes in the biosynthesis of lecithin (phosphatidylcholine). Biochim Biophys Acta 46(2):205–216. https://doi.org/10.1016/0006-3002(61)90745-4
Brosnan J, Brosnan M (2006). The sulfur-containing amino acids: an overview. J Nutr 136(6 Suppl):1636S–1640S. https://doi.org/10.1093/jn/136.6.1636S
Burton A, Azevedo C, Andreassi C, Riccio A, Saiardi A (2013) Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation. Proc Natl Acad Sci USA 110(47):18970–18975
Chakraborty A, Kim S, Snyder S (2011) Inositol pyrophosphates as mammalian cell signals. Sci Signal 4(188):re1. https://doi.org/10.1126/scisignal.2001958
Clarke J, Letcher A, D’santos C, Halstead J, Irvine R, Divecha N (2001) Inositol lipids are regulated during cell cycle progression in the nuclei of murine erythroleukaemia cells. Biochem J 357:905–910. https://doi.org/10.1042/0264-6021:3570905
D’Santos C, Clarke J, Divecha N (1998) Phospholipid signalling in the nucleus: Een DAG uit het leven van de inositide signalering in de nucleus. Biochim Biophys Acta 1436(1–2):201–232
Draskovic P, Saiardi A, Bhandari R, Burton A, Ilc G, Kovacevic M, Snyder S, Podobnik M (2008) Inositol hexakisphosphate kinase products contain diphosphate and triphosphate groups. Chem Biol 15(3):274–286. https://doi.org/10.1016/j.chembiol.2008.01.011
Essafi A, Webb A, Berry R, Sligh J, Burn S, Spraggon L, Velecela V, Martinez-Estrada O, Wiltshire J, Roberts S, Brownstein D, Davies J, Hastie N, Hohenstein P (2011) A wt1-controlled chromatin switching mechanism underpins tissue-specific wnt4 activation and repression. Dev Cell 21(3):559–574. https://doi.org/10.1016/j.devcel.2011.07.014
Gelato KA, Tauber M, Ong MS, Winter S, Hiragami-Hamada K, Sindlinger J, Lemak A, Bultsma Y, Houliston S, Schwarzer D, Divecha N, Arrowsmith CH, Fischle W (2014) Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate. Mol Cell 54(6):905–919. https://doi.org/10.1016/j.molcel.2014.04.004
Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA, Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG, Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J (2003) The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell 114(1):99–111
Hait N, Allegood J, Maceyka M, Strub G, Harikumar K, Singh S, Luo C, MArmorstein R, Kordula T, Milstien S, Spiegel S (2009) Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325(5945):1254–1257. https://doi.org/10.1126/science.1176709
Hamann B, Blind R (2018) Nuclear phosphoinositide regulation of chromatin. J Cell Physiol 233(1):107–123. https://doi.org/10.1002/jcp.25886
Hickman M, Petti A, Ho-Shing O, Silverman S, McIsaac R, Lee T, Botstein D (2011) Coordinated regulation of sulfur and phospholipid metabolism reflects the importance of methylation in the growth of yeast. Mol Biol Cell 22(21):4192–4204. https://doi.org/10.1091/mbc.E11-05-0467
Irvine R, Divecha N (1992) Phospholipids in the nucleus-metabolism and possible functions. Semin Cell Biol 3(4):225–235
Jacob R, Stead L, Devlin C, Tabas I, Brosnan M, Brosnan J, Vance D (2005) Physiological regulation of phospholipid methylation alters plasma homocysteine in mice. J Biol Chem 280(31):28299–28305. https://doi.org/10.1074/jbc.M501971200
Jones DR, Bultsma Y, Keune WJ, Halstead JR, Elouarrat D, Mohammed S, Heck AJ, D’Santos CS, Divecha N (2006) Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta. Mol Cell 23(5):685–695. https://doi.org/10.1016/j.molcel.2006.07.014
Jungmichel S, Sylvestersen KB, Choudhary C, Nguyen S, Mann M, Nielsen ML (2014) Specificity and commonality of the phosphoinositide-binding proteome analyzed by quantitative mass spectrometry. Cell Rep 6(3):578–591. https://doi.org/10.1016/j.celrep.2013.12.038
Kashihara M, Miyata S, Kumanogoh H, Funatsu N, Matsunaga W, Kiyohara T, Sokawa Y, Maekawa S (2000) Changes in the localization of NAP-22, a calmodulin binding membrane protein, during the development of neuronal polarity. Neurosci Res 37(4):315–325
Kutateladze T (2012) Histone deacetylation: IP4 is a epigenetic coregulator. Nat Chem Biol 8(3):230–231. https://doi.org/10.1038/nchembio.795
Lemmon M (2007) Pleckstrin homology (PH) domains and phosphoinositides. Biochem Soc Symp 74:81–93. https://doi.org/10.1042/BSS0740081
Lewis AE, Sommer L, Arntzen M, Strahm Y, Morrice NA, Divecha N, D’Santos CS (2011). Identification of nuclear phosphatidylinositol 4,5-bisphosphate-interacting proteins by neomycin extraction. Mol Cell Proteomics. https://doi.org/10.1074/mcp.M110.003376
Lin H, Fridy P, Ribeiro A, Choi J, Barma D, Vogel G, Falck J, Shears S, York JD, Mayr G (2009) Structural analysis and detection of biological inositol pyrophosphates reveal that the family of VIP/diphosphoinositol pentakisphosphate kinases are 1/3-kinases. J Biol Chem 284(3):1863–1872. https://doi.org/10.1074/jbc.M805686200
Maceyka M, Sankala H, Hait N, Le Stunff H, Liu H, Toman R, Collier C, Zhang M, Satin L, Merrill AJ, Milstien S, Spiegel S (2005) SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem 280(44):37118–37129. https://doi.org/10.1074/jbc.M502207200
Maceyka M, Harikumar K, Milstien S, Spiegel S (2012) Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol 22(1):50–56é. https://doi.org/10.1016/j.tcb.2011.09.003
Maekawa S, Murofushi H, Nakamura S (1994) Inhibitory effect of calmodulin on phosphorylation of NAP-22 with protein kinase C. J Biol Chem 269(30):19462–19465
Maraldi N, Santi S, Zini N, Ognibene A, Rizzoli R, Mazzotti G, Di Primio R, Bareggi R, Bertagnolo V, Pagliarini C (1993) Decrease in nuclear phospholipids associated with DNA replication. J Cell Sci 104(3):853–859
Maraldi N., Zini N., Santi S. and Manzoli F. (1999). Topology of inositol lipid signal transduction in the nucleus. J Cell Physiol 181(2):203–217. https://doi.org/10.1002/(SICI)1097-4652(199911)181:2<203::AID-JCP3>3.0.CO;2-O
Margueron R, Trojer P, Reinberg D (2005) The key to development: interpreting the histone code? Curr Opin Genet Dev 15(2):163–176. https://doi.org/10.1016/j.gde.2005.01.005
Mazzotti G, Zini N, Rizzi E, Rizzoli R, Galanzi A, Ognibene A, Santi S, Matteucci A, Martelli AM, Maraldi NM (1995) Immunocytochemical detection of phosphatidylinositol 4,5-bisphosphate localization sites within the nucleus. J Histochem Cytochem 43(2):181–191
Mellman DL, Gonzales ML, Song CH, Barlow CA, Wang P, Kendziorski C, Anderson RA (2008) A PtdIns4,5P(2)-regulated nuclear poly(A) polymerase controls expression of select mRNAs. Nature 451(7181):U1013–U1019. https://doi.org/10.1038/nature06666
Millard C, Watson P, Celardo I, Gordiyenko Y, Cowley S, Robinson C, Fairall L, Schwabe J (2013) Class I HDACs share a common mechanism of regulation by inositol phosphates. Mol Cell 51(1):57–67. https://doi.org/10.1016/j.molcel.2013.05.020
Monserrate J, York J (2010) Inositol phospahte synthesis and the nuclear processes they affect. Curr Opin Cell Biol 22(3):365–373. https://doi.org/10.1016/j.ceb.2010.03.006
Mortier E, Wuytens G, Leenaerts I, Hannes F, Heung MY, Degeest G, David G, Zimmermann P (2005) Nuclear speckles and nucleoli targeting by PIP2–PDZ domain interactions. EMBO J 24(14):2556–2565
Mosevitsky M, Capony J, Skladchikova G, Novitskaya V, Plekhanov A, Zakharov V (1997) The BASP1 family of myristoylated proteins abundant in axonal termini. Primary structure analysis and physico-chemical properties. Biochimie 79(6):373–384
Ndamukong I, Jones D, Lapko H, Divecha N, Avramova Z (2010) Phosphatidylinositol 5-phosphate links dehydration stress to the activity of Arabidopsis trithorax-like factor ATX1. PLoS One 5(10):e13396. https://doi.org/10.1371/journal.pone.0013396
Osborne SL, Thomas CL, Gschmeissner S, Schiavo G (2001) Nuclear PtdIns(4,5)P2 assembles in a mitotically regulated particle involved in pre-mRNA splicing. J Cell Sci 114(Pt 13):2501–2511
Peitzsch R, McLaughlin S (1993) Binding of acylated peptides and fatty acids to phospholipid vesicles: pertinence to myristoylated proteins. Biochemistry 32(39):10436–10443
Rando O, Zhao K, Janmey P, Crabtree G (2002) Phosphatidylinositol-dependent actin filament binding by the SWI/SNF-like BAF chromatin remodeling complex. Proc Natl Acad Sci USA 99:2824–2829. https://doi.org/10.1073/pnas.032662899
Sadhu M, Moresco J, Zimmer A, Yates Jr, Rine J (2014) Multiple inputs control sulfur-containing amino acid synthesis in Saccharomyces cerevisiae. Mol Biol Cell 25(10):1653–1665. https://doi.org/10.1091/mbc.E13-12-0755
Sairadi A, Nagata E, Hongbo R, Sawa A, Luo X, Snowman A, Snyder S (2001) Mammalian inositol polyphosphate multikinase synthesizes inositol 1,4,5-trisphosphate and an inositol pyrophosphate. Proc Natl Acad Sci USA 98(5):2306–2311. https://doi.org/10.1073/pnas.041614598
Sato M, Ueda Y, Shibuya M, Umezawa Y (2005) Locating inositol 1,4,5-trisphosphate in the nucleus and neuronal dendrites with genetically encoded fluorescent indicators. Anal Chem 77(15):4751–4758
Seto E, Yoshida M (2014) Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol 6(4):a018713. https://doi.org/10.1101/cshperspect.a018713
Shears S (2015) Inositol pyrophosphates: why so many phosphates? Adv Biol Regul 57:203–216. https://doi.org/10.1016/j.jbior.2014.09.015
Sobol M, Yildirim S, Philimonenko VV, Marášek P, Castaño E, Hozák P (2013) UBF complexes with phosphatidylinositol 4,5-bisphosphate in nucleolar organizer regions regardless of ongoing RNA polymerase I activity. Nucleus 4(6):478–486. https://doi.org/10.4161/nucl.27154
Sobol M, Krausová A, Yildirim S, Kalasová I, Fáberová V, Vrkoslav V, Philimonenko V, Marášek P, Pastorek L, Čapek M, Lubovská Z, Uličná L, Tsuji T, Hozak P (2018) Nuclear phosphatidylinositol 4,5-bisphosphate islets contribute to efficient RNA polymerase II-dependent transcription. J Cell Sci. https://doi.org/10.1242/jcs.211094
Stefan C, Trimble W, Grinstein S, Drin G, Reinisch K, De Camilli P, Cohen S, Valm A, Lippincott-Schwartz J, Levine T, Iaea D, Maxfield F, Futter C, Eden E, Judith D, van Vliet A, Agostinis P, Tooze S, Sugiura A, McBride H (2017). Membrane dynamics and organelle biogenesis-lipid pipelines and vesicular carriers. BMC Biol. https://doi.org/10.1186/s12915-017-0432-0
Stipanuk M (2004) Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr 24:539–577
Strub G, Maceyka M, Hait N, Milstien S, Spiegel S (2010) Extracellular and intracellular actions of sphingosine-1-phosphate. Adv Exp Med Biol 688:141–155
Sutter B, Wu X, Laxman S, Tu B (2013) Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A. Cell 154(2):403–415. https://doi.org/10.1016/j.cell.2013.06.041
Takasaki A, Hayashi N, Matsubara M, Yamauchi E, Taniguchi H (1999) Identification of the calmodulin-binding domain of neuron-specific protein kinase C substrate protein CAP-22/NAP-22. Direct involvement of protein myristoylation in calmodulin-target protein interaction. J Biol Chem 274(17):11848–11853
Toska E, Campbell HA, Shandilya J, Goodfellow SJ, Shore P, Medler KF, Roberts SG (2012) Repression of transcription by WT1-BASP1 requires the myristoylation of BASP1 and the PIP2-dependent recruitment of histone deacetylase. Cell Rep 2(3):462–469. https://doi.org/10.1016/j.celrep.2012.08.005
Tran D, Gascard P, Berthon B, Fukami K, Takenawa T, Giraud F, Claret M (1993) Cellular distribution of polyphosphoinositides in rat hepatocytes. Cell Signal 5:565–581. https://doi.org/10.1016/0898-6568(93)90052-N
Ulicna L, Kalendova A, Kalasova I, Vacik T, Hozák P (2018) PIP2 epigenetically represses rRNA genes transcription interacting with PHF8. Biochim Biophys Acta 1863(3):266–275. https://doi.org/10.1016/j.bbalip.2017.12.008
Ungewickell A, Hugge C, Kisseleva M, Chang S, Zou J, Feng Y, Galyov E, Wilson M, Majerus P (2005) The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases. Proc Natl Acad Sci USA 102:18854–18859. https://doi.org/10.1073/pnas.0509740102
Vance D (2014) Phospholipid methylation in mammals: from biochemistry to physiological function. Biochim Biophys Acta 1838(6):1477–1487. https://doi.org/10.1016/j.bbamem.2013.10.018
Vance J, Tasseva G (2013) Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells. Biochim Biophys Acta 1831(3):543–554. https://doi.org/10.1016/j.bbalip.2012.08.016
Vann L, Wooding F, Irvine R, Divecha N (1997) Metabolism and possible compartmentalization of inositol lipids in isolated rat-liver nuclei. Biochem J 327(2):569–576. https://doi.org/10.1042/bj3270569
Viiri K, Maki M, Lohi O (2012). Phosphoinositides as regulators of protein–chromatin interactions. Sci Signal. https://doi.org/10.1126/scisignal.2002917
Watson P, Fairall L, Santos G, Schwabe J (2012) Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature 481(7381):335–340
Watson P, Millard C, Riley A, Robertson N, Wright L, Godage H, Cowley S, Jamieson A, Potter B, Schwabe J (2016). Insights into the activation mechanism of class I HDAC complexes by inositol phosphates. Nat Commun. https://doi.org/10.1038/ncomms11262
Watt SA, Kular G, Fleming IN, Downes CP, Lucocq JM (2002) Subcellular localization of phosphatidylinositol 4,5-bisphosphate using the pleckstrin homology domain of phospholipase C delta1. Biochem J 363(Pt 3):657–666
Wilson M, Livermore T, Saiardi A (2013) Inositol pyrophosphates: between signalling and metabolism. Biochem J 452(3):369–379. https://doi.org/10.1042/BJ20130118
Ye C, Sutter B, Wang Y, Kuang Z, Tu B (2017) A metabolic function for phospholipid and histone methylation. Mol Cell 66(2):180–193. https://doi.org/10.1016/j.molcel.2017.02.026
Yildirim S, Castano E, Sobol M, Philimonenko VV, Dzijak R, Venit T, Hozák P (2013) Involvement of PIP2 in RNA polymerase I transcription. J Cell Sci 126(Pt 12):2730–2739. https://doi.org/10.1242/jcs.123661
York J, Majerus P (1994) Nuclear phosphatidylinositols decrease during S-phase of the cell cycle in HeLa cells. J Biol Chem 269(11):7847–7850
Yu HY, Fukami K, Watanabe Y, Ozaki C, Takenawa T (1998) Phosphatidylinositol 4,5-bisphosphate reverses the inhibition of RNA transcription caused by histone H1. Eur J Biochem 251(1–2):281–287. https://doi.org/10.1046/j.1432-1327.1998.2510281.x
Zhao K, Wang W, Rando O, Xue Y, Swiderek K, Kuo A, Crabtree G (1998) Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95(5):625–636
Zolov SN, Bridges D, Zhang Y, Lee WW, Riehle E, Verma R, Lenk GM, Converso-Baran K, Weide T, Albin RL, Saltiel AR, Meisler MH, Russell MW, Weisman LS (2012) In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P. Proc Natl Acad Sci USA 109(43):17472–17477. https://doi.org/10.1073/pnas.1203106109
Acknowledgements
This work was supported by the Grant Agency of the Czech Republic (Grant nos. 15-08738S; 16-03346S and 17-09103S); by the Czech Academy of Sciences (Grant no. JSPS-18-18) and the Institutional Research Concept of the Institute of Molecular Genetics (Grant no. RVO: 68378050). This work was supported by the project “BIOCEV—Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University” (CZ.1.05/1.1.00/02.0109), from the European Regional Development Fund. This work was supported by the Microscopy Centre; Light/Electron CF, IMG CAS supported by the MEYS CR (LM2015062 Czech-BioImaging). The work is supported from European Regional Development Fund-Project “Modernization and support of research activities of the national infrastructure for biological and medical imaging Czech-BioImaging” (no. CZ.02.1.01/0.0/0.0/16_013/0001775).
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Uličná, L., Paprčková, D., Fáberová, V. et al. Phospholipids and inositol phosphates linked to the epigenome. Histochem Cell Biol 150, 245–253 (2018). https://doi.org/10.1007/s00418-018-1690-9
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DOI: https://doi.org/10.1007/s00418-018-1690-9