PGRMC1 phosphorylation status and cell plasticity 2: genomic integrity and CpG methylation

Background: During vertebrate embryology the state of animal cell differentiation is determined by several mechanisms, including heritable but plastic patterns of genomic and histone methylation. Cancer is a disease related to loss of terminal differentiation. Progesterone receptor membrane component 1 (PGRMC1) is a protein that has been implicated in cancer biology and poor patient outcomes. It can be over-expressed in cancers, and exist in alternative states of phosphorylation. A motif centered on PGRMC1 Y180 was evolutionarily acquired in animals by the common ancestor of Cnidaria and bilateral animals, concomitantly with an embryological organizer of gastrulation associated with the induction of systematically regulated epigenetic genome methylation. Results: Here, we show that manipulation of PGRMC1 phosphorylation by mutagenesis results in altered cell metabolism, genomic stability, and CpG methylation. Hypothesizing that PGRMC1 phosphorylation status affects genome methylation, we discovered that each of several mutants elicited distinct patterns of CpG methylation. Mutation of Y180 led to increased overall hypermethylation levels, accompanied by hypomethylation of selected promoter- and cell-type enhancers, reminiscent of the hypermethylated status of embryonic stem cells. Pathways enrichment analysis suggested modulation of processes related to animal cell differentiation status and tissue identity, as well as cell cycle control and ATM/ATR DNA damage repair regulation. We detected PGRMC1 phospho-status-dependent differential rates of genomic mutation after thirty culture passages. Conclusions: In companion manuscripts we show that 1) these cell states are associated with dramatic effects on protein abundances, cell and mitochondrial morphology, and glycolytic metabolism, and 2) that Y180 has been evolutionarily conserved since its simultaneous appearance with the animal gastrulation organizer. These combined studies suggest that PGRMC1 phosphorylation status, as controlled by ill-defined signaling processes affected by phosphorylation site mutants, modulates cellular plasticity by affecting mechanisms relevant to early embryological tissue differentiation, which should be highly relevant to disease.