AJMB  Vol.4 No.4 , October 2014
Leptin Signaling Modulates Expression of Polycomb and Trithorax Complexes in the Brain of Fat Tissue Implanted Polycystic Ovarian Sindrome Mice
ABSTRACT
The Polycystic Ovary Syndrome (PCOS) is the most common androgenic disorder in women during reproductive life. PCOS may also be accompanied by metabolic syndrome and recent studies point to leptin as playing a role in disrupting infertility and in changing the energy balance in obese mice through its action on the hypothalamus. The aim is to assess the expression of the Polycomb & Trithorax Complexes genes in brain of mice transplanted with fat tissue from normal mice, in order to better understand the neuronal mechanisms underlying the reversion of PCOS. Three B6 V-Lepob/J mouse groups: Normal weight, obese and seven-day-treatment obese had their brain RNA extracted and submitted to an 84 Polycomb & Trithorax Complexes genes PCR Array plate and MetacoreTM pathways localization. Genomic profiles obtained were compared to the ones of the normal-weight-mice group. Differentially expressed genes were 13% and 26% respectively to control and treatment. Major changes were in genes: Snai1/31; Smarca1/?17; Dnmt3b/4.7; Ezh1/ 15. Altered genes were associated to canonical pathways and provided 3 networks related to epigenetics. Underlying neuronal changes caused by leptin in obese mice brain, there is an important role being played by the histone code. Here there is evidence that leptin drives the chromatin packing to a more condensed pattern. Upregulation of methyltransferase genes, like Ezh1, favors this thought. In summary the Polycomb & Trithorax complexes might answer for the silencing of some downregulated genes in the obese mice brain when exposed to leptin.

Cite this paper
Freitas, E. , Noronha, S. , Ritto, M. , Baptista, C. , Silva, I. , Correa-Noronha, S. and Silva, I. (2014) Leptin Signaling Modulates Expression of Polycomb and Trithorax Complexes in the Brain of Fat Tissue Implanted Polycystic Ovarian Sindrome Mice. American Journal of Molecular Biology, 4, 177-192. doi: 10.4236/ajmb.2014.44020.
References
[1]   Pasquali, R. and Gambineri, A. (2013) Insulin Sensitizers in Polycystic Ovary Syndrome. Frontiers of Hormone Research, 40, 83-102. http://dx.doi.org/10.1159/000341837

[2]   Hahn, S., Bering van Halteren, W., Roesler, S., Schmidt, M., Kimmig, R., Tan, S., Mann, K. and Janssen, O.E. (2006) The Combination of Increased Ovarian Volume and Follicle Number Is Associated with More Severe Hyperandr Ogenism in German Women with Polycystic Ovary Syndrome. Experimental and Clinical Endocrinology & Diabetes, 114, 175-181. http://dx.doi.org/10.1055/s-2006-924063

[3]   Premoli, A.C., Santana, L.F., Ferriani, R.A., Moura, M.D., DeSa, M.F. and Reis, R.M. (2005) Growth Hormone Secretion and Insulin-Like Growth Factor-1 Are Related to Hyperandrogenism in Nonobese Patients with Polycystic Ovary Syndrome. Fertility and Sterility, 83, 1852-1855.
http://dx.doi.org/10.1016/j.fertnstert.2004.10.057

[4]   Lomniczi, A., Loche, A., Castellano, J.M., Ronnekleiv, O.K., Bosch, M., Kaidar, G., Knoll, J.G., Wright, H., Pfeifer, G.P. and Ojeda, S.R. (2003) Epigenetic Control of Female Puberty. Nature Neuroscience, 16, 281-289.

[5]   Yagi, S., Hirabayashi, K., Sato, S., Li, W., Takahashi, Y., Hirakawa, T., Wu, G., Hattori, N., Hattori, N., Ohgane, J., Tanaka, S., Liu, X.S. and Shiota, K. (2008) DNA Methylation Profile of Tissue-Dependent and Differentially Methylated Regions (T-DMRs) in Mouse Promoter Regions Demonstrating Tissue-Specific Gene Expression. Genome Research, 18, 1969-1978. http://dx.doi.org/10.1101/gr.074070.107

[6]   Hattori, N., Nishino, K., Ko, Y.G., Hattori, N., Ohgane, J., Tanaka, S. and Shiota, K. (2004). Epigenetic Control of Mouse Oct-4 Gene Expression in Embryonic Stem Cells and Trophoblast Stem Cells. Journal of Biological Chemistry, 279, 17063-17069. http://dx.doi.org/10.1074/jbc.M309002200

[7]   Ikegami, K., Ohgane, J., Tanaka, S., Yagi, S. and Shiota, K. (2009) Interplay between DNA Methylation, Histone Modification and Chromatin Remodeling in Stem Cells and during Development. International Journal of Developmental Biology, 53, 203-214. http://dx.doi.org/10.1387/ijdb.082741ki

[8]   Ohgane, J., Hattori, N., Oda, M., Tanaka, S. and Shiota, K. (2002) Differentiation of Trophoblast Lineage Is Associated with DNA Methylation and Demethylation. Biochemical and Biophysical Research Communications, 290, 701-706. http://dx.doi.org/10.1006/bbrc.2001.6258

[9]   Shiota, C., Larsson, O., Shelton, K.D., et al. (2002) Sulfonylurea Receptor Type 1 Knock-Out Mice Have Intact Feeding-Stimulated Insulin Secretion Despite Marked Impairment in Their Response to GlucoseJournal of Biological Chemistry, 277, 37176-37183.

[10]   Shogren-Knaak, M., Ishii, H., Sun, J.M., Pazin, M.J., Davie, J.R. and Peterson, C.L. (2006) Histone H4-K16 Acetylation Controls Chromatin Structure and Protein Interactions. Science, 311, 844-847.
http://dx.doi.org/10.1126/science.1124000

[11]   Baskind, H.A., Na, L., Ma, Q., Patel, M.P., Geenen, D.L. and Wang, Q.T. (2009) Functional Conservation of Asxl2, a Murine Homolog for the Drosophila Enhancer of Trithorax and Polycomb Gene Asx. PLoS ONE, 4, e4750. http://dx.doi.org/10.1371/journal.pone.0004750

[12]   Escargueil, A.E., Soares, D.G., Salvador, M., Larsen, A.K. and Henriques, J.A. (2008) What Histone Code for DNA Repair? Mutation Research/Reviews in Mutation Research, 658, 259-270.
http://dx.doi.org/10.1016/j.mrrev.2008.01.004

[13]   Czermin, B., Melfi, R., McCabe, D., Seitz, V., Imhof, A. and Pirrotta, V. (2002) Drosophila Enhancer of Zeste/ESC Complexes Have a Histone H3 Methyltransferase Activity That Marks Chromosomal Polycomb Sites. Cell, 111, 185-196. http://dx.doi.org/10.1016/S0092-8674(02)00975-3

[14]   Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P. and Reinberg, D. (2002) Histone Methyltransferase Activity Associated with a Human Multiprotein Complex Containing the Enhancer of Zeste Protein. Genes & Development, 16, 2893-2905. http://dx.doi.org/10.1101/gad.1035902

[15]   Ikegami, K., Ohgane, J., Tanaka, S., Yagi, S. and Shiota, K. (2009) Interplay between DNA Methylation, Histone Modification and Chromatin Remodeling in Stem Cells and during Development. International Journal of Developmental Biology, 53, 203-214. http://dx.doi.org/10.1387/ijdb.082741ki

[16]   Schuettengruber, B., Chourrout, D., Vervoort, M., Leblanc, B. and Cavalli, G. (2007) Genome Regulation by Polycomb and Trithorax Proteins. Cell, 128, 735-745. http://dx.doi.org/10.1016/j.cell.2007.02.009

[17]   Yokoyama, A., Wang, Z., Wysocka, J., Sanyal, M., Aufiero, D.J., Kitabayashi, I., et al. (2004) Leukemia Proto-Oncoprotein MLL Forms a SET1-Like Histone Methyltransferase Complex with Menin to Regulate Hox Gene Expression. Molecular and Cellular Biology, 24, 5639-5649.
http://dx.doi.org/10.1128/MCB.24.13.5639-5649.2004

[18]   Bernstein, B.E., Kamal, M., Lindblad-Toh, K., Bekiranov, S., Bailey, D.K., Huebert, D.J., et al. (2005) Genomic Maps and Comparative Analysis of Histone Modifications in Human and Mouse. Cell, 120, 169-181. http://dx.doi.org/10.1016/j.cell.2005.01.001

[19]   Schneider, R., Bannister, A.J., Myers, F.A., Thorne, A.W., Crane-Robinson, C. and Kouzarides, T. (2004) Histone H3 Lysine 4 Methylation Patterns in Higher Eukaryotic Genes. Nature Cell Biology, 6, 73-77. http://dx.doi.org/10.1038/ncb1076

[20]   Yoo, A.S. and Crabtree, G.R. (2009) ATP-Dependent Chromatin Remodeling in Neural Development. Current Opinion in Neurobiology, 19, 120-126. http://dx.doi.org/10.1016/j.conb.2009.04.006

[21]   Nakamura, T., Mori, T., Tada, S., Krajewski, W., Rozovskaia, T., Wassell, R., et al. (2002) ALL-1 Is a Histone Methyltransferase That Assembles a Supercomplex of Proteins Involved in Transcriptional Regulation. Molecular Cell, 10, 1119-1128. http://dx.doi.org/10.1016/S1097-2765(02)00740-2

[22]   Prezioso, C. and Orlando, V. (2011) Polycomb Proteins in Mammalian Cell Differentiation and Plasticity. FEBS Letters, 585, 2067-2077.

[23]   Margueron, R., Li, G., Sarma, K., Blais, A., Zavadil, J., Woodcock, C.L., Dynlacht, B.D. and Reinberg, D. (2008) Ezh1 and Ezh2 Maintain Repressive Chromatin through Different Mechanisms. Molecular Cell, 32, 503-518.

[24]   Zhuge, X., Kataoka, H., Tanaka, M., Murayama, T., Kawamoto, T., Sano, H., Togi, K., Yamauchi, R., Ueda, Y., Xu, Y., Nishikawa, S., Kita, T. and Yokode, M. (2005) Expression of the Novel Snai-Related Zinc-Finger Transcription Factor Gene Smuc during Mouse Development. International Journal of Molecular Medicine, 15, 945-948.

[25]   Nasonkin, I.O., Lazo, K., Hambright, D., Brooks, M., Fariss, R. and Swaroop, A. (2011) Distinct Nuclear Localization Patterns of DNA Methyltransferases in Developing and Mature Mammalian Retina. Journal of Comparative Neurology, 519, 1914-1930.

[26]   Lazzaro, M.A. and Picketts, D.J. (2001) Cloning and Characterization of the Murine Imitation Switch (ISWI) Genes: Differential Expression Patterns Suggest Distinct Developmental Roles for Snf2h and Snf2l. Journal of Neurochemistry, 77, 1145-1156.

[27]   Begum, G., Davies, A., Stevens, A., Oliver, M., Jaquiery, A., Challis, J., Harding, J., Bloomfield, F. and White, A. (2013) Maternal Undernutrition Programs Tissue Specific Epigenetic Changes in the Glucocorticoid Receptor in Adult Offspring. Endocrinology, 154, 4560-4569.

[28]   De Giorgio, M.R., Yoshioka, M. and St-Amand, J. (2009) Feeding Induced Changes in the Hypothalamic Transcriptome. Clinica Chimica Acta, 406, 103-107.

[29]   Makedonski, K., Abuhatzira, L., Kaufman, Y., Razin, A. and Shemer, R. (2005) MeCP2 Deficiency in Rett Syndrome Causes Epigenetic Aberrations at the PWS/AS Imprinting Center That Affects UBE3A Expression. Human Molecular Genetics, 14, 1049-1058.

[30]   Vincenz, C. and Kerppola, T.K. (2008) Different Polycomb Group CBX Family Proteins Associate with Distinct Regions of Chromatin Using Nonhomologous Protein Sequences. Proceedings of the National Academy of Sciences of the United States of America, 105, 16572-16577.

[31]   Zhao, L.J., Subramanian, T. and Chinnadurai, G. (2006) Changes in C-Terminal Binding Protein 2 (CtBP2) Corepressor Complex Induced by E1A and Modulation of E1A Transcriptional Activity by CtBP2. The Journal of Biological Chemistry, 281, 36613-36623.

[32]   Murphy, T.M., Mullins, N., Ryan, M., Foster, T., Kelly, C., McClelland, R., O’Grady, J., Corcoran, E., Brady, J., Reilly, M., Jeffers, A., Brown, K., Maher, A., Bannan, N., Casement, A., Lynch, D., Bolger, S., Buckley, A., Quinlivan, L., Daly, L., Kelleher, C. and Malone, K.M. (2013) Genetic Variation in DNMT3B and Increased Global DNA Methylation Is Associated with Suicide Attempts in Psychiatric Patients. Genes, Brain and Behavior, 12, 125-132.

[33]   Lomniczi, A., Wright, H., Castellano, J.M., Sonmez, K. and Ojeda, S.R. (2013) A System Biology Approach to Identify Regulatory Pathways Underlying the Neuroendocrine Control of Femalepuberty in Rats and Nonhuman Primates. Hormones and Behavior, 64, 175-186.
http://dx.doi.org/10.1016/j.yhbeh.2012.09.013

[34]   Mousavi, K., Zare, H., Wang, A.H. and Sartorelli, V. (2012) Polycomb Protein Ezh1 Promotes RNA Polymerase II Elongation. Molecular Cell, 45, 255-262.

[35]   Seo, J., Kim, K., Chang, D.Y., Kang, H.B., Shin, E.C., Kwon, J. and Choi, J.K. (2014) Genome Wide Reorganization of Histone H2AX toward Particular Fragile Sites on Cell Activation. Nucleic Acids Research, 42, 1016-1025.

[36]   Takeuchi, T., Watanabe, Y., Takano-Shimizu, T. and Kondo, S. (2006) Roles of Jumonji and Jumonji Family Genes in Chromatin Regulation and Development. Developmental Dynamics, 235, 2449-2459.

[37]   Peterlin, B.M., Brogie, J.E. and Price, D.H. (2012) 7SK snRNA: A Noncoding RNA That Plays a Major Role in Regulating Eukaryotic Transcription. Wiley Interdisciplinary Reviews: RNA, 3, 92-103.

[38]   LaFave, M.C., Varshney, G.K., Gildea, D.E., Wolfsberg, T.G., Baxevanis, A.D. and Burgess, S.M. (2014) MLV Integration Site Selection Is Driven by Strong Enhancers and Active Promoters. Nucleic Acids Research, 42, 4257-4269. http://dx.doi.org/10.1093/nar/gkt1399

[39]   Junco, S.E., Wang, R., Gaipa, J.C., Taylor, A.B., Schirf, V., Gearhart, M.D., Bardwell, V.J., Demeler, B., Hart, P.J. and Kim, C.A. (2013) Structure of the Polycomb Group Protein PCGF1 in Complex with BCOR Reveals Basis for Binding Selectivity of PCGF Homologs. Structure, 21, 665-671.

[40]   Stapels, M., Piper, C., Yang, T., Li, M., Stowell, C., Xiong, Z.G., Saugstad, J., Simon, R.P., Geromanos, S., Langridge, J., Lan, J.Q. and Zhou, A. (2010) Polycomb Group Proteins as Epigenetic Mediators of Neuroprotection in Ischemic Tolerance. Science Signaling, 3, ra15.

[41]   Lee, Y.H., Kim, S.H., Lee, Y.J., Kang, E.S., Lee, B.W., Cha, B.S., Kim, J.W., Song, D.H. and Lee, H.C. (2013) Transcription Factor Snail Is a Novel Regulator of Adipocyte Differentiation via Inhibiting the Expression of Peroxisome Proliferator-Activated Receptor γ. Cellular and Molecular Life Sciences, 70, 3959-3971.

[42]   Zaman, M.M., Nomura, T., Takagi, T., Okamura, T., Jin, W., Shinagawa, T., Tanaka, Y. and Ishii, S. (2013) Ubiquitination-Deubiquitination by the TRIM27-USP7 Complex Regulates Tumor Necrosis Factor α-Induced Apoptosis. Molecular and Cellular Biology, 33, 4971-4984.

[43]   Xiao, X., Tang, C., Xiao, S., Fu, C. and Yu, P. (2013) Enhancement of Proliferation and Invasion by MicroRNA-590-5p via Targeting PBRM1 in Clear Cell Renal Carcinoma Cells. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, 20, 537-544.
http://dx.doi.org/10.3727/096504013X13775486749335

[44]   Shore, A.N., Kabotyanski, E.B., Roarty, K., Smith, M.A., Zhang, Y., Creighton, C.J., Dinger, M.E. and Rosen, J.M. (2012) Pregnancy-Induced Noncoding RNA (PINC) Associates with Polycomb Repressive Complex 2 and Regulates Mammary Epithelial Differentiation. Plos Genetics, 8, e1002840.
http://dx.doi.org/10.1371/journal.pgen.1002840

[45]   Marei, H.E,. Ahmed, A.E., Michetti, F., Pescatori, M., Pallini, R., Casalbore, P., Cenciarelli, C. and Elhadidy, M. (2012) Gene Expression Profile of Adult Human Olfactory Bulb and Embryonic Neural Stem Cell Suggests Distinct Signaling Pathways and Epigenetic Control. PLoS ONE, 7, e33542.
http://dx.doi.org/10.1371/journal.pone.0033542

[46]   Austenaa, L., Barozzi, I., Chronowska, A., Termanini, A., Ostuni, R., Prosperini, E., Stewart, A.F., Testa, G. and Natoli, G. (2012) The Histone Methyltransferase Wbp7 Controls Macrophage Function through GPI Glycolipid Anchor Synthesis. Immunity, 36, 572-585.

[47]   Kingston, R.E. and Tamkun, J.W. (2014) Transcriptional Regulation by Trithorax-Group Proteins. Cold Spring Harbor Perspectives in Biology, 6, pii: a019349. http://dx.doi.org/10.1101/cshperspect.a019349

[48]   Ringrose, L. and Paro, R. (2007) Polycomb/Trithorax Response Elements and Epigenetic Memory of Cell Identity. DeVelopment, 134, 223-232. http://dx.doi.org/10.1242/dev.02723

[49]   Levine, S.S., Weiss, A., Erdjument-Bromage, H., Shao, Z., Tempst, P. and Kingston, R.E. (2002) The Core of the Polycomb Repressive Complex Is Compositionally and Functionally Conserved in Flies and Humans. Molecular and Cellular Biology, 22, 6070-6078.
http://dx.doi.org/10.1128/MCB.22.17.6070-6078.2002

[50]   Kia, S.K., Gorski, M.M., Giannakopoulos, S. and Verrijzer, C.P. (2008) SWI/SNF Mediates Polycomb Eviction and Epigenetic Reprogramming of the INK4b-ARF-INK4a Locus. Molecular and Cellular Biology, 28, 3457-3464. http://dx.doi.org/10.1128/MCB.02019-07

[51]   Francis, N.J., Kingston, R.E. and Woodcock, C.L. (2004) Chromatin Compaction by a Polycomb Group Protein Complex. Science, 306, 1574-1577.

[52]   Wang, H., Wang, L., Erdjument-Bromage, H., Vidal, M., Tempst, P., Jones, R.S. and Zhang, Y. (2004) Role of Histone H2A Ubiquitination in Polycomb Silencing. Nature, 431, 873-878.
http://dx.doi.org/10.1038/nature02985

[53]   Bernstein, E., Duncan, E.M., Masui, O., Gil, J., Heard, E. and Allis, C.D. (2006) Mouse Polycomb Proteins Bind Differentially to Methylated Histone H3 and RNA and Are Enriched in Facultative Heterochromatin. Molecular and Cellular Biology, 26, 2560-2569.
http://dx.doi.org/10.1128/MCB.26.7.2560-2569.2006

[54]   Fiskus, W., Pranpat, M., Balasis, M., Herger, B., Rao, R., Chinnaiyan, A., Atadja, P. and Bhalla, K. (2006) Histone Deacetylase Inhibitors Deplete Enhancer of Zeste 2 and Associated Polycomb Repressive Complex 2 Proteins in Human Acute Leukemia Cells. Molecular Cancer Therapeutics, 5, 3096-3104.

[55]   Wang, L., Brown, J.L., Cao, R., Zhang, Y., Kassis, J.A. and Jones, R.S. (2004) Hierarchical Recruitment of Polycomb Group Silencing Complexes. Molecular Cell, 14, 637-646.
http://dx.doi.org/10.1016/j.molcel.2004.05.009

[56]   Schoeftner, S., Sengupta, A.K., Kubicek, S., Mechtler, K., Spahn, L., Koseki, H., Jenuwein, T. and Wutz, A. (2006) Recruitment of PRC1 Function at the Initiation of X Inactivation Independent of PRC2 and Silencing. The EMBO Journal, 25, 3110-3122. http://dx.doi.org/10.1038/sj.emboj.7601187

[57]   Boyer, L.A., Plath, K., Zeitlinger, J., Brambrink, T., Medeiros, L.A., Lee, T.I., Levine, S.S., Wernig, M., Tajonar, A., Ray, M.K., et al. (2006) Polycomb Complexes Repress Developmental Regulators in Murine Embryonic Stem Cells. Nature, 441, 349-353. http://dx.doi.org/10.1038/nature04733

[58]   Bracken, A.P., Dietrich, N., Pasini, D., Hansen, K.H. and Helin, K. (2006) Genome-Wide Mapping of Polycomb Target Genes Unravels Their Roles in Cell Fate Transitions. Genes & Development, 20, 1123-1136. http://dx.doi.org/10.1101/gad.381706

[59]   Lee, T.I., Jenner, R.G., Boyer, L.A., Guenther, M.G., Levine, S.S., Kumar, R.M., Chevalier, B., Johnstone, S.E., Cole, M.F., Isono, K., et al. (2006) Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells. Cell, 125, 301-313. http://dx.doi.org/10.1016/j.cell.2006.02.043

[60]   Squazzo, S.L., O’Geen, H., Komashko, V.M., Krig, S.R., Jin, V.X., Jang, S.W., Margueron, R., Reinberg, D., Green, R. and Farnham, P.J. (2006) Suz12 Binds to Silenced Regions of the Genome in a Cell-Type-Specific Manner. Genome Research, 16, 890-900. http://dx.doi.org/10.1101/gr.5306606

[61]   Whitcomb, S.J., Basu, A., Allis, C.D. and Bernstein, E. (2007) Polycomb Group Proteins: An Evolutionary Perspective. Trends in Genetics, 23, 494-502. http://dx.doi.org/10.1016/j.tig.2007.08.006

[62]   Cao, Q., Wang, X., Zhao, M., Yang, R., Malik, R., Qiao, Y., Poliakov, A., Yocum, A.K., Li, Y., Chen, W., Cao, X., Jiang, X., Dahiya, A., Harris, C., Feng, F.Y., Kalantry, S., Qin, Z.S., Dhanasekaran, S.M. and Chinnaiyan, A.M. (2014) The Central Role of EED in the Orchestration of Polycomb Group Complexes. Nature Communications, 5, Article No. 3127. http://dx.doi.org/10.1038/ncomms4127

[63]   Ho, L. and Crabtree, G.R. (2008) An EZ Mark to Miss. Cell Stem Cell, 3, 577-578.

[64]   Blumenberg, M., Gao, S., Dickman, K., Grollman, A.P., Bottinger, E.P. and Zavadil, J. (2007) Chromatin Structure Regulation in Transforming Growth Factor-β-Directed Epithelial-Mesenchymal Transition. Cells Tissues Organs, 185, 162-174. http://dx.doi.org/10.1159/000101317

[65]   Han, Z., Xing, X., Hu, M., Zhang, Y., Liu, P. and Chai, J. (2007) Structural Basis of EZH2 Recognition by EED. Structure, 15, 1306-1315. http://dx.doi.org/10.1016/j.str.2007.08.007

[66]   MuhChyi, C., Juliandi, B., Matsuda, T. and Nakashima, K. (2013) Epigenetic Regulation of Neural Stem Cell Fate during Corticogenesis. International Journal of Developmental Neuroscience, 31, 424-433. http://dx.doi.org/10.1016/j.ijdevneu.2013.02.006

 
 
Top