Demethylation of the Protein Phosphatase PP2A Promotes Demethylation of Histones to Enable Their Function as a Methyl Group Sink

Mol Cell. 2019 Mar 21;73(6):1115-1126.e6. doi: 10.1016/j.molcel.2019.01.012. Epub 2019 Feb 13.


Dysregulation of chromatin methylation is associated with defects in cellular differentiation as well as a variety of cancers. How cells regulate the opposing activities of histone methyltransferase and demethylase enzymes to set the methylation status of the epigenome for proper control of gene expression and metabolism remains poorly understood. Here, we show that loss of methylation of the major phosphatase PP2A in response to methionine starvation activates the demethylation of histones through hyperphosphorylation of specific demethylase enzymes. In parallel, this regulatory mechanism enables cells to preserve SAM by increasing SAH to limit SAM consumption by methyltransferase enzymes. Mutants lacking the PP2A methyltransferase or the effector H3K36 demethylase Rph1 exhibit elevated SAM levels and are dependent on cysteine due to reduced capacity to sink the methyl groups of SAM. Therefore, PP2A directs the methylation status of histones by regulating the phosphorylation status of histone demethylase enzymes in response to SAM levels.

Keywords: SAM; chromatin; demethylation; epigenetics; histones; metabolism; methylation; signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin / genetics
  • Chromatin / metabolism*
  • DNA Methylation*
  • Dealkylation
  • Gene Expression Regulation, Fungal
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism
  • Histones / metabolism*
  • Methylation
  • Mutation
  • Protein Binding
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Protein Processing, Post-Translational*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • S-Adenosylmethionine / metabolism
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*


  • Chromatin
  • Histones
  • RPH1 protein, S cerevisiae
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • S-Adenosylmethionine
  • Histone Demethylases
  • Protein Phosphatase 2