General principle and importance of organization of chromosome structures during mammalian development and cell differentiation

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In mammals, DNA methylation is an important epigenetic mark that is associated with chromosome construction. Using a DNA methylation inhibitor, we found that reduced levels of DNA methylation were associated with the activation of transcription from centromere regionsand a shift in replication timing of the pericenromeric regions from middle/late S to early S phase through depositing histone H3.3 on pericenromeric heterochromatin prior to the accumulation of the euchromatic histone modification, suggesting that DNA methylation is essential for proper organization of pericentromeric heterochromatin in differentiated mouse cells. We also found that DNA methyltransferase 1 knockdown or inhibition causes replication fork stalling and replication-associated DNA damages. We propose that replication stress in the course of passive DNA demethylation could be a source of spontaneous mutations and genomic instability during tumorigenesis and aging.