Developmental control of tumor suppressor gene methylation

Methylation at CpG dinucleotides, the best undersood epigenetic mechanism in mammals, allows cells to silence transcription of particular genes in a relatively stable manner. The inverse correlation between gene expression and methylation levels at CpG islands, promoter elements enriched in CpG sequences, has been seen in several contexts. For instance, the persistent silencing of one allele of imprinted genes or large regions of one X chromosome in normal female cells are associated with hypermethylation. A similar process seems to be at work during tumorigenesis in the epigenetic silencing of certain growth inhibitory genes. This effect has been documented with the tumor suppressor genes p16 and p15,whose products INK4a and INK4b are well known inhibitors of cyclin dependent kinases. These genes each carry CpG islands in their promoters, which become hypermethylated in various tumors. Sakeshita et al. now show that this process mirrors events in normal development, when p15 is silenced by methylation during hematopoesis. Methylation, they find, occurs in an all-or-none fashion throughout the CpG island and correlates with a developmental switch whereby hematopoietic precursor cells become committed to forming granulocytes and monocytes. This epigenetic change is transient and apparently specific for p15, since p16 remains unmethylated throughout. The authors also show that global inhibition of CpG methylation favors the proliferation of hematopoietic precursor cells and blocks their differentiation along the myeloid lineage. This work raises critical questions about the nature and regulation of the demethylases that erase p15 methylation in these cells

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