Epigenetic systems are well known for the roles they play in regulating the differential expression of the same genome in different cell types. However, epigenetic systems can also directly impact genomic integrity by protecting genetic sequences. Using an experimental evolutionary approach, we studied rates of mutation in the fission yeast Schizosaccharomyces pombe strains that lacked genes encoding several epigenetic regulators or mismatch repair components. We report that loss of a functional mismatch repair pathway in S. pombe resulted in the preferential enrichment of mutations in euchromatin, indicating that the mismatch repair machinery preferentially protected genetic fidelity in euchromatin. This preference is probably determined by differences in the accessibility of chromatin at distinct chromatin regions, which is supported by our observations that chromatin accessibility positively correlated with mutation rates in S. pombe or human cancer samples with deficiencies in mismatch repair. Importantly, such positive correlation was not observed in S. pombe strains or human cancer samples with functional mismatch repair machinery.