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

Rachelle Irwin, Avinash Thakur, Karla O'Neill, CP Walsh

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)
6 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)383-92
Number of pages10
JournalGenomics
Volume104
Issue number5
Early online date29 Aug 2014
DOIs
Publication statusPublished - Nov 2014

Bibliographical 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

Keywords

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

Fingerprint

Dive into the research topics of '5-Hydroxymethylation marks a class of neuronal gene regulated by intragenic methylcytosine levels.'. Together they form a unique fingerprint.

Cite this