5-Hydroxymethylation marks a class of neuronal gene regulated by intragenic methylcytosine levels.

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

We recently identified a class of neuronal gene inheriting high levels of intragenic methylation from the mother and maintaining this through later development. We show here that these genes are implicated in basic neuronal functions such as post-synaptic signalling, rather than neuronal development and inherit high levels of 5mC, but not 5hmC, from the mother. 5mC is distributed across the gene body and appears to facilitate transcription, as transcription is reduced in DNA methyltransferase I (Dnmt1) knockout embryonic stem cells as well as in fibroblasts treated with a methyltransferase inhibitor. However in adult brain, transcription is more closely associated with a gain in 5hmC, which occurs without a measurable loss of 5mC. These findings add to growing evidence that there may be a role for 5mC in promoting transcription as well as its classical role in gene silencing.
LanguageEnglish
Pages383-92
JournalGenomics
Volume104
Issue number5
DOIs
Publication statusPublished - Nov 2014

Fingerprint

Methyltransferases
Genes
Gene Silencing
Embryonic Stem Cells
Methylation
Fibroblasts
DNA
Brain

Keywords

  • Epigenetics
  • 5′-Methylcytosine
  • 5′-Hydroxymethylation
  • Neuronal function
  • Gametes
  • Development

Cite this

@article{7a9a67678d754c4584a5f7ef94f195ab,
title = "5-Hydroxymethylation marks a class of neuronal gene regulated by intragenic methylcytosine levels.",
abstract = "We recently identified a class of neuronal gene inheriting high levels of intragenic methylation from the mother and maintaining this through later development. We show here that these genes are implicated in basic neuronal functions such as post-synaptic signalling, rather than neuronal development and inherit high levels of 5mC, but not 5hmC, from the mother. 5mC is distributed across the gene body and appears to facilitate transcription, as transcription is reduced in DNA methyltransferase I (Dnmt1) knockout embryonic stem cells as well as in fibroblasts treated with a methyltransferase inhibitor. However in adult brain, transcription is more closely associated with a gain in 5hmC, which occurs without a measurable loss of 5mC. These findings add to growing evidence that there may be a role for 5mC in promoting transcription as well as its classical role in gene silencing.",
keywords = "Epigenetics, 5′-Methylcytosine, 5′-Hydroxymethylation, Neuronal function, Gametes, Development",
author = "Rachelle Irwin and CP Walsh",
note = "Reference text: [1] Y.F. He, B.Z. Li, Z. Li, P. Liu, Y. Wang, Q. Tang, J. Ding, Y. Jia, Z. Chen, L. Li, Y. Sun, X. Li, Q. Dai, C.X. Song, K. Zhang, C. He, G.L. Xu, Tet-mediated formation of 5- carboxylcytosine and its excision by TDG in mammalian DNA, Science 333 (2011) 1303–1307. [2] H. Hashimoto, S. Hong, A.S. Bhagwat, X. Zhang, X. Cheng, Excision of 5- hydroxymethyluracil and 5-carboxylcytosine by the thymine DNA glycosylase domain: its structural basis and implications for active DNA demethylation, Nucleic Acids Res. 40 (2012) 10203–10214. [3] L. Shen, H. Wu, D. Diep, S. Yamaguchi, A.C. D'Alessio, H.L. Fung, K. Zhang, Y. Zhang, Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics, Cell 153 (2013) 692–706. [4] G. Ficz, M.R. Branco, S. Seisenberger, F. Santos, F. Krueger, T.A. Hore, C.J. Marques, S. Andrews, W. Reik, Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation, Nature 473 (2011) 398–402. [5] T.P. Gu, F. Guo, H. Yang, H.P. Wu, G.F. Xu, W. Liu, Z.G. Xie, L. Shi, X. He, S.G. Jin, K. Iqbal, Y.G. Shi, Z. Deng, P.E. Szabo, G.P. Pfeifer, J. Li, G.L. Xu, The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes, Nature 477 (2011) 606–610. [6] R.R. Zhang, Q.Y. Cui, K. Murai, Y.C. Lim, Z.D. Smith, S. Jin, P. Ye, L. Rosa, Y.K. Lee, H.P. Wu, W. Liu, Z.M. Xu, L. Yang, Y.Q. Ding, F. Tang, A. Meissner, C. Ding, Y. Shi, G.L. Xu, Tet1 regulates adult hippocampal neurogenesis and cognition, Cell Stem Cell 13 (2013) 237–245. [7] M.A. Hahn, R. Qiu, X. Wu, A.X. Li, H. Zhang, J. Wang, J. Jui, S.G. Jin, Y. Jiang, G.P. Pfeifer, Q. Lu, Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis, Cell. Rep. 3 (2013) 291–300. [8] R. Lister, E.A. Mukamel, J.R. Nery, M. Urich, C.A. Puddifoot, N.D. Johnson, J. Lucero, Y. Huang, A.J. Dwork, M.D. Schultz, M. Yu, J. Tonti-Filippini, H. Heyn, S. Hu, J.C. Wu, A. Rao, M. Esteller, C. He, F.G. Haghighi, T.J. Sejnowski, M.M. Behrens, J.R. Ecker, Global epigenomic reconfiguration during mammalian brain development, Science 341 (2013) 1237905. [9] F. Neri, A. Krepelova, D. Incarnato, M. Maldotti, C. Parlato, F. Galvagni, F. Matarese, H. G. Stunnenberg, S. Oliviero, Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs, Cell 155 (2013) 121–134. [10] H. Wu, V. Coskun, J. Tao, W. Xie, W. Ge, K. Yoshikawa, E. Li, Y. Zhang, Y.E. Sun, Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes, Science 329 (2010) 444–448. [11] J.P. Thomson, P.J. Skene, J. Selfridge, T. Clouaire, J. Guy, S. Webb, A.R. Kerr, A. Deaton, R. Andrews, K.D. James, D.J. Turner, R. Illingworth, A. Bird, CpG islands influence chromatin structure via the CpG-binding protein Cfp1, Nature 464 (2010) 1082–1086. [12] A.K. Maunakea, R.P. Nagarajan, M. Bilenky, T.J. Ballinger, C. D'Souza, S.D. Fouse, B. E. Johnson, C. Hong, C. Nielsen, Y. Zhao, G. Turecki, A. Delaney, R. Varhol, N. Thiessen, K. Shchors, V.M. Heine, D.H. Rowitch, X. Xing, C. Fiore, M. Schillebeeckx, S.J. Jones, D. Haussler, M.A. Marra, M. Hirst, T. Wang, J.F. Costello, Conserved role of intragenic DNA methylation in regulating alternative promoters, Nature 466 (2010) 253–257. [13] R.S. Illingworth, U. Gruenewald-Schneider, S. Webb, A.R. Kerr, K.D. James, D.J. Turner, C. Smith, D.J. Harrison, R. Andrews, A.P. Bird, Orphan CpG islands identify numerous conserved promoters in the mammalian genome, PLoS Genet. 6 (2010) e1001134. [14] W. Huang da, B.T. Sherman, R.A. Lempicki, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources, Nat. Protoc. 4 (2009) 44–57. [15] W. Huang da, B.T. Sherman, R.A. Lempicki, Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists, Nucleic Acids Res. 37 (2009) 1–13. [16] C.E. Rutledge, A. Thakur, K.M. O'Neill, R.E. Irwin, S. Sato, K. Hata, C.P. Walsh, Ontogeny, conservation and functional significance of maternally inherited DNA methylation at two classes of non-imprinted genes, Development 141 (2014) 1313–1323. [17] S.A. Smallwood, S. Tomizawa, F. Krueger, N. Ruf, N. Carli, A. Segonds-Pichon, S. Sato, K. Hata, S.R. Andrews, G. Kelsey, Dynamic CpG island methylation landscape in oocytes and preimplantation embryos, Nat. Genet. 43 (2011) 811–814. [18] H. Kobayashi, T. Sakurai, M. Imai, N. Takahashi, A. Fukuda, O. Yayoi, S. Sato, K. Nakabayashi, K. Hata, Y. Sotomaru, Y. Suzuki, T. Kono, Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks, PLoS Genet. 8 (2012) e1002440. [19] A. Szwagierczak, S. Bultmann, C.S. Schmidt, F. Spada, H. Leonhardt, Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA, Nucleic Acids Res. 38 (2010) e181. [20] E. Dobbin, P.M. Corrigan, C.P. Walsh, M.J. Welham, R.W. Freeburn, H. Wheadon, Tel/PDGFRbeta inhibits self-renewal and directs myelomonocytic differentiation of ES cells, Leuk. Res. 32 (2008) 1554–1564. [21] S. Hitoshi, R.M. Seaberg, C. Koscik, T. Alexson, S. Kusunoki, I. Kanazawa, S. Tsuji, D. van der Kooy, Primitive neural stem cells from the mammalian epiblast differentiate R.E. Irwin et al. / Genomics 104 (2014) 383–392 391 to definitive neural stem cells under the control of Notch signaling, Genes Dev. 18 (2004) 1806–1811. [22] K. Woodfine, J.E. Huddleston, A. Murrell, Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue, Epigenetics Chromatin. 4 (2011) 1. [23] S.G. Jin, X. Wu, A.X. Li, G.P. Pfeifer, Genomic mapping of 5-hydroxymethylcytosine in the human brain, Nucleic Acids Res. 39 (2011) 5015–5024. [24] J.E. Loughery, P.D. Dunne, K.M. O'Neill, R.R. Meehan, J.R. McDaid, C.P. Walsh, DNMT1 deficiency triggers mismatch repair defects in human cells through depletion of repair protein levels in a process involving the DNA damage response, Hum. Mol. Genet. 20 (2011) 3241–3255. [25] C.E. Nestor, R. Ottaviano, J. Reddington, D. Sproul, D. Reinhardt, D. Dunican, E. Katz, J. M. Dixon, D.J. Harrison, R.R. Meehan, Tissue type is a major modifier of the 5- hydroxymethylcytosine content of human genes, Genome Res. 22 (2012) 467–477. [26] S.A. Smallwood, G. Kelsey, De novo DNA methylation: a germ cell perspective, Trends Genet. 28 (2012) 33–42. [27] B. Giardine, C. Riemer, R.C. Hardison, R. Burhans, L. Elnitski, P. Shah, Y. Zhang, D. Blankenberg, I. Albert, J. Taylor, W. Miller, W.J. Kent, A. Nekrutenko, Galaxy: a platform for interactive large-scale genome analysis, Genome Res. 15 (2005) 1451–1455. [28] J.Y. Li, D.J. Lees-Murdock, G.L. Xu, C.P. Walsh, Timing of establishment of paternal methylation imprints in the mouse, Genomics 84 (2004) 952–960. [29] D.J. Lees-Murdock, H.T. Lau, D.H. Castrillon, M. De Felici, C.P. Walsh, DNA methyltransferase loading, but not de novo methylation, is an oocyte-a",
year = "2014",
month = "11",
doi = "10.1016/j.ygeno.2014.08.013",
language = "English",
volume = "104",
pages = "383--92",
number = "5",

}

5-Hydroxymethylation marks a class of neuronal gene regulated by intragenic methylcytosine levels. / Irwin, Rachelle; Walsh, CP.

Vol. 104, No. 5, 11.2014, p. 383-92.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 5-Hydroxymethylation marks a class of neuronal gene regulated by intragenic methylcytosine levels.

AU - Irwin, Rachelle

AU - Walsh, CP

N1 - Reference text: [1] Y.F. He, B.Z. Li, Z. Li, P. Liu, Y. Wang, Q. Tang, J. Ding, Y. Jia, Z. Chen, L. Li, Y. Sun, X. Li, Q. Dai, C.X. Song, K. Zhang, C. He, G.L. Xu, Tet-mediated formation of 5- carboxylcytosine and its excision by TDG in mammalian DNA, Science 333 (2011) 1303–1307. [2] H. Hashimoto, S. Hong, A.S. Bhagwat, X. Zhang, X. Cheng, Excision of 5- hydroxymethyluracil and 5-carboxylcytosine by the thymine DNA glycosylase domain: its structural basis and implications for active DNA demethylation, Nucleic Acids Res. 40 (2012) 10203–10214. [3] L. Shen, H. Wu, D. Diep, S. Yamaguchi, A.C. D'Alessio, H.L. Fung, K. Zhang, Y. Zhang, Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics, Cell 153 (2013) 692–706. [4] G. Ficz, M.R. Branco, S. Seisenberger, F. Santos, F. Krueger, T.A. Hore, C.J. Marques, S. Andrews, W. Reik, Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation, Nature 473 (2011) 398–402. [5] T.P. Gu, F. Guo, H. Yang, H.P. Wu, G.F. Xu, W. Liu, Z.G. Xie, L. Shi, X. He, S.G. Jin, K. Iqbal, Y.G. Shi, Z. Deng, P.E. Szabo, G.P. Pfeifer, J. Li, G.L. Xu, The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes, Nature 477 (2011) 606–610. [6] R.R. Zhang, Q.Y. Cui, K. Murai, Y.C. Lim, Z.D. Smith, S. Jin, P. Ye, L. Rosa, Y.K. Lee, H.P. Wu, W. Liu, Z.M. Xu, L. Yang, Y.Q. Ding, F. Tang, A. Meissner, C. Ding, Y. Shi, G.L. Xu, Tet1 regulates adult hippocampal neurogenesis and cognition, Cell Stem Cell 13 (2013) 237–245. [7] M.A. Hahn, R. Qiu, X. Wu, A.X. Li, H. Zhang, J. Wang, J. Jui, S.G. Jin, Y. Jiang, G.P. Pfeifer, Q. Lu, Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis, Cell. Rep. 3 (2013) 291–300. [8] R. Lister, E.A. Mukamel, J.R. Nery, M. Urich, C.A. Puddifoot, N.D. Johnson, J. Lucero, Y. Huang, A.J. Dwork, M.D. Schultz, M. Yu, J. Tonti-Filippini, H. Heyn, S. Hu, J.C. Wu, A. Rao, M. Esteller, C. He, F.G. Haghighi, T.J. Sejnowski, M.M. Behrens, J.R. Ecker, Global epigenomic reconfiguration during mammalian brain development, Science 341 (2013) 1237905. [9] F. Neri, A. Krepelova, D. Incarnato, M. Maldotti, C. Parlato, F. Galvagni, F. Matarese, H. G. Stunnenberg, S. Oliviero, Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs, Cell 155 (2013) 121–134. [10] H. Wu, V. Coskun, J. Tao, W. Xie, W. Ge, K. Yoshikawa, E. Li, Y. Zhang, Y.E. Sun, Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes, Science 329 (2010) 444–448. [11] J.P. Thomson, P.J. Skene, J. Selfridge, T. Clouaire, J. Guy, S. Webb, A.R. Kerr, A. Deaton, R. Andrews, K.D. James, D.J. Turner, R. Illingworth, A. Bird, CpG islands influence chromatin structure via the CpG-binding protein Cfp1, Nature 464 (2010) 1082–1086. [12] A.K. Maunakea, R.P. Nagarajan, M. Bilenky, T.J. Ballinger, C. D'Souza, S.D. Fouse, B. E. Johnson, C. Hong, C. Nielsen, Y. Zhao, G. Turecki, A. Delaney, R. Varhol, N. Thiessen, K. Shchors, V.M. Heine, D.H. Rowitch, X. Xing, C. Fiore, M. Schillebeeckx, S.J. Jones, D. Haussler, M.A. Marra, M. Hirst, T. Wang, J.F. Costello, Conserved role of intragenic DNA methylation in regulating alternative promoters, Nature 466 (2010) 253–257. [13] R.S. Illingworth, U. Gruenewald-Schneider, S. Webb, A.R. Kerr, K.D. James, D.J. Turner, C. Smith, D.J. Harrison, R. Andrews, A.P. Bird, Orphan CpG islands identify numerous conserved promoters in the mammalian genome, PLoS Genet. 6 (2010) e1001134. [14] W. Huang da, B.T. Sherman, R.A. Lempicki, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources, Nat. Protoc. 4 (2009) 44–57. [15] W. Huang da, B.T. Sherman, R.A. Lempicki, Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists, Nucleic Acids Res. 37 (2009) 1–13. [16] C.E. Rutledge, A. Thakur, K.M. O'Neill, R.E. Irwin, S. Sato, K. Hata, C.P. Walsh, Ontogeny, conservation and functional significance of maternally inherited DNA methylation at two classes of non-imprinted genes, Development 141 (2014) 1313–1323. [17] S.A. Smallwood, S. Tomizawa, F. Krueger, N. Ruf, N. Carli, A. Segonds-Pichon, S. Sato, K. Hata, S.R. Andrews, G. Kelsey, Dynamic CpG island methylation landscape in oocytes and preimplantation embryos, Nat. Genet. 43 (2011) 811–814. [18] H. Kobayashi, T. Sakurai, M. Imai, N. Takahashi, A. Fukuda, O. Yayoi, S. Sato, K. Nakabayashi, K. Hata, Y. Sotomaru, Y. Suzuki, T. Kono, Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks, PLoS Genet. 8 (2012) e1002440. [19] A. Szwagierczak, S. Bultmann, C.S. Schmidt, F. Spada, H. Leonhardt, Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA, Nucleic Acids Res. 38 (2010) e181. [20] E. Dobbin, P.M. Corrigan, C.P. Walsh, M.J. Welham, R.W. Freeburn, H. Wheadon, Tel/PDGFRbeta inhibits self-renewal and directs myelomonocytic differentiation of ES cells, Leuk. Res. 32 (2008) 1554–1564. [21] S. Hitoshi, R.M. Seaberg, C. Koscik, T. Alexson, S. Kusunoki, I. Kanazawa, S. Tsuji, D. van der Kooy, Primitive neural stem cells from the mammalian epiblast differentiate R.E. Irwin et al. / Genomics 104 (2014) 383–392 391 to definitive neural stem cells under the control of Notch signaling, Genes Dev. 18 (2004) 1806–1811. [22] K. Woodfine, J.E. Huddleston, A. Murrell, Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue, Epigenetics Chromatin. 4 (2011) 1. [23] S.G. Jin, X. Wu, A.X. Li, G.P. Pfeifer, Genomic mapping of 5-hydroxymethylcytosine in the human brain, Nucleic Acids Res. 39 (2011) 5015–5024. [24] J.E. Loughery, P.D. Dunne, K.M. O'Neill, R.R. Meehan, J.R. McDaid, C.P. Walsh, DNMT1 deficiency triggers mismatch repair defects in human cells through depletion of repair protein levels in a process involving the DNA damage response, Hum. Mol. Genet. 20 (2011) 3241–3255. [25] C.E. Nestor, R. Ottaviano, J. Reddington, D. Sproul, D. Reinhardt, D. Dunican, E. Katz, J. M. Dixon, D.J. Harrison, R.R. Meehan, Tissue type is a major modifier of the 5- hydroxymethylcytosine content of human genes, Genome Res. 22 (2012) 467–477. [26] S.A. Smallwood, G. Kelsey, De novo DNA methylation: a germ cell perspective, Trends Genet. 28 (2012) 33–42. [27] B. Giardine, C. Riemer, R.C. Hardison, R. Burhans, L. Elnitski, P. Shah, Y. Zhang, D. Blankenberg, I. Albert, J. Taylor, W. Miller, W.J. Kent, A. Nekrutenko, Galaxy: a platform for interactive large-scale genome analysis, Genome Res. 15 (2005) 1451–1455. [28] J.Y. Li, D.J. Lees-Murdock, G.L. Xu, C.P. Walsh, Timing of establishment of paternal methylation imprints in the mouse, Genomics 84 (2004) 952–960. [29] D.J. Lees-Murdock, H.T. Lau, D.H. Castrillon, M. De Felici, C.P. Walsh, DNA methyltransferase loading, but not de novo methylation, is an oocyte-a

PY - 2014/11

Y1 - 2014/11

N2 - We recently identified a class of neuronal gene inheriting high levels of intragenic methylation from the mother and maintaining this through later development. We show here that these genes are implicated in basic neuronal functions such as post-synaptic signalling, rather than neuronal development and inherit high levels of 5mC, but not 5hmC, from the mother. 5mC is distributed across the gene body and appears to facilitate transcription, as transcription is reduced in DNA methyltransferase I (Dnmt1) knockout embryonic stem cells as well as in fibroblasts treated with a methyltransferase inhibitor. However in adult brain, transcription is more closely associated with a gain in 5hmC, which occurs without a measurable loss of 5mC. These findings add to growing evidence that there may be a role for 5mC in promoting transcription as well as its classical role in gene silencing.

AB - We recently identified a class of neuronal gene inheriting high levels of intragenic methylation from the mother and maintaining this through later development. We show here that these genes are implicated in basic neuronal functions such as post-synaptic signalling, rather than neuronal development and inherit high levels of 5mC, but not 5hmC, from the mother. 5mC is distributed across the gene body and appears to facilitate transcription, as transcription is reduced in DNA methyltransferase I (Dnmt1) knockout embryonic stem cells as well as in fibroblasts treated with a methyltransferase inhibitor. However in adult brain, transcription is more closely associated with a gain in 5hmC, which occurs without a measurable loss of 5mC. These findings add to growing evidence that there may be a role for 5mC in promoting transcription as well as its classical role in gene silencing.

KW - Epigenetics

KW - 5′-Methylcytosine

KW - 5′-Hydroxymethylation

KW - Neuronal function

KW - Gametes

KW - Development

U2 - 10.1016/j.ygeno.2014.08.013

DO - 10.1016/j.ygeno.2014.08.013

M3 - Article

VL - 104

SP - 383

EP - 392

IS - 5

ER -