In cases where proteins comprise different properties, like combining writer or
eraser functions with reader abilities, targeting the respective reader domain should
also be considered as an alternative to the so-far preferred aim of influencing the
enzymatic reader or eraser process. It will be interesting to address the question
if inhibitors of the reader-histone interaction will phenocopy the inhibition of the
enzymatic activity. This strategy would potentially preserve enzymatic nonhistone
activities of the respective protein which could help in avoiding possible side effects
that might occur upon the treatment of a specific phenotype.
Compliance with Ethical Standards
Funding: G.S. is supported by grants from the Italian Ministero dell’Istruzione, dell’Università e
della Ricerca (MIUR), Progetti di Ricerca di Interesse Nazionale (PRIN 20152TE5PK), and from
the Università di Salerno (Italy), and by European Cooperation in Science and Technology (COST
Action CM1406).
Conflict of Interest: The author declares no competing financial interests.
Ethical Statement: This article does not contain any studies with human participants or animals
performed by any of the authors.
References
1. Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T, Pillus L, Reinberg D, Shi Y,
Shiekhattar R, Shilatifard A, Workman J, Zhang Y (2007) New nomenclature for chromatinmodifying enzymes. Cell 131(4):633–636. https://doi.org/10.1016/j.cell.2007.10.039
2. Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol
Cell Biol 6(11):838–849. https://doi.org/10.1038/nrm1761
3. Smith BC, Denu JM (2009) Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta 1789(1):45–57. https://doi.org/10.1016/j.bbagrm.2008.06.005
4. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding
modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct
Mol Biol 14(11):1025–1040. https://doi.org/10.1038/nsmb1338
5. Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, and
why. Mol Cell 33(1):1–13. https://doi.org/10.1016/j.molcel.2008.12.013
6. Chang B, Chen Y, Zhao Y, Bruick RK (2007) JMJD6 is a histone arginine demethylase.
Science 318(5849):444–447. https://doi.org/10.1126/science.1145801
7. Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B, Nielsen ML, Schmitz C,
Butler DS, Yates JR 3rd, Delahunty CM, Hahn P, Lengeling A, Mann M, Proudfoot NJ,
Schofield CJ, Bottger A (2009) Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein
associated with RNA splicing. Science 325(5936):90–93. https://doi.org/10.1126/science.
1175865
8. Gayatri S, Bedford MT (2014) Readers of histone methylarginine marks. Biochim Biophys
Acta 1839(8):702–710. https://doi.org/10.1016/j.bbagrm.2014.02.015
9. Hughes RM, Waters ML (2006) Arginine methylation in a beta-hairpin peptide: implications
for Arg-pi interactions, DeltaCp(o), and the cold denatured state. J Am Chem Soc 128
(39):12735–12742. https://doi.org/10.1021/ja061656g
10. Lee DY, Teyssier C, Strahl BD, Stallcup MR (2005) Role of protein methylation in regulation
of transcription. Endocr Rev 26(2):147–170. https://doi.org/10.1210/er.2004-0008
Methyl-Readers and Inhibitors
383
eraser functions with reader abilities, targeting the respective reader domain should
also be considered as an alternative to the so-far preferred aim of influencing the
enzymatic reader or eraser process. It will be interesting to address the question
if inhibitors of the reader-histone interaction will phenocopy the inhibition of the
enzymatic activity. This strategy would potentially preserve enzymatic nonhistone
activities of the respective protein which could help in avoiding possible side effects
that might occur upon the treatment of a specific phenotype.
Compliance with Ethical Standards
Funding: G.S. is supported by grants from the Italian Ministero dell’Istruzione, dell’Università e
della Ricerca (MIUR), Progetti di Ricerca di Interesse Nazionale (PRIN 20152TE5PK), and from
the Università di Salerno (Italy), and by European Cooperation in Science and Technology (COST
Action CM1406).
Conflict of Interest: The author declares no competing financial interests.
Ethical Statement: This article does not contain any studies with human participants or animals
performed by any of the authors.
References
1. Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T, Pillus L, Reinberg D, Shi Y,
Shiekhattar R, Shilatifard A, Workman J, Zhang Y (2007) New nomenclature for chromatinmodifying enzymes. Cell 131(4):633–636. https://doi.org/10.1016/j.cell.2007.10.039
2. Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol
Cell Biol 6(11):838–849. https://doi.org/10.1038/nrm1761
3. Smith BC, Denu JM (2009) Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta 1789(1):45–57. https://doi.org/10.1016/j.bbagrm.2008.06.005
4. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding
modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct
Mol Biol 14(11):1025–1040. https://doi.org/10.1038/nsmb1338
5. Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, and
why. Mol Cell 33(1):1–13. https://doi.org/10.1016/j.molcel.2008.12.013
6. Chang B, Chen Y, Zhao Y, Bruick RK (2007) JMJD6 is a histone arginine demethylase.
Science 318(5849):444–447. https://doi.org/10.1126/science.1145801
7. Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B, Nielsen ML, Schmitz C,
Butler DS, Yates JR 3rd, Delahunty CM, Hahn P, Lengeling A, Mann M, Proudfoot NJ,
Schofield CJ, Bottger A (2009) Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein
associated with RNA splicing. Science 325(5936):90–93. https://doi.org/10.1126/science.
1175865
8. Gayatri S, Bedford MT (2014) Readers of histone methylarginine marks. Biochim Biophys
Acta 1839(8):702–710. https://doi.org/10.1016/j.bbagrm.2014.02.015
9. Hughes RM, Waters ML (2006) Arginine methylation in a beta-hairpin peptide: implications
for Arg-pi interactions, DeltaCp(o), and the cold denatured state. J Am Chem Soc 128
(39):12735–12742. https://doi.org/10.1021/ja061656g
10. Lee DY, Teyssier C, Strahl BD, Stallcup MR (2005) Role of protein methylation in regulation
of transcription. Endocr Rev 26(2):147–170. https://doi.org/10.1210/er.2004-0008
Methyl-Readers and Inhibitors
383