Demethylation of the protein phosphatase PP2A promotes demethylation of histones to enable their function as a methyl group sink

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.

染色质甲基化失调与细胞分化缺陷及多种癌症密切相关。目前学界对细胞如何调控组蛋白甲基转移酶与去甲基化酶的拮抗活性，以精准设定表观基因组的甲基化状态，进而实现对基因表达与代谢的合理调控这一过程，仍知之甚少。本研究表明，在甲硫氨酸饥饿条件下，主要磷酸酶PP2A的甲基化缺失会通过特异性去甲基化酶的过度磷酸化，激活组蛋白去甲基化进程。与此同时，该调控机制可通过提升S-腺苷同型半胱氨酸（SAH）的水平，限制甲基转移酶对SAM的消耗，从而维持细胞内SAM的稳态。缺失PP2A甲基转移酶或组蛋白H3K36去甲基化酶Rph1的突变体，其S-腺苷甲硫氨酸（SAM）水平显著升高；且由于清除SAM甲基基团的能力下降，这些突变体对半胱氨酸产生依赖。综上，PP2A可通过响应SAM水平调控组蛋白去甲基化酶的磷酸化状态，进而决定组蛋白的甲基化修饰状态。