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CG hypomethylation in Lsh−/− mouse embryonic fibroblasts is associated with de novo H3K4me1 formation and altered cellular plasticity

Significance Cytosine methylation is an epigenetic mark dynamically regulated during embryogenesis and associated with the establishment of tissue specific enhancers. Despite the close relationship, whether CG hypomethylation can influence enhancer formation and cellular identity remains unclear. Using a DNA methylation mutant mouse model, the Lsh−/− mice with approximately 50% site-specific reduction of CG methylation, we provide evidence for a link between CG hypomethylation and poised enhancers that can acquire functional activity and regulate lineage commitment. Our data suggests a pathway of how alterations in the methylome can influence cellular differentiation. DNA methylation patterns are established in early embryogenesis and are critical for cellular differentiation. To investigate the role of CG methylation in potential enhancer formation, we assessed H3K4me1 modification in murine embryonic fibroblasts (MEFs) derived from the DNA methylation mutant Lsh−/− mice. We report here de novo formation of putative enhancer elements at CG hypomethylated sites that can be dynamically altered. We found a subset of differentially enriched H3K4me1 regions clustered at neuronal lineage genes and overlapping with known cis-regulatory elements present in brain tissue. Reprogramming of Lsh−/− MEFs into induced pluripotent stem (iPS) cells leads to increased neuronal lineage gene expression of premarked genes and enhanced differentiation potential of Lsh−/− iPS cells toward the neuronal lineage pathway compared with WT iPS cells in vitro and in vivo. The state of CG hypomethylation and H3K4me1 enrichment is partially maintained in Lsh−/− iPS cells. The acquisition of H3K27ac and activity of subcloned fragments in an enhancer reporter assay indicate functional activity of several of de novo H3K4me1-marked sequences. Our results suggest a functional link of H3K4me1 enrichment at CG hypomethylated sites, enhancer formation, and cellular plasticity.