Summary DNA methylation was described almost a century ago. However, the rules governing its establishment and maintenance remain elusive. Here, we present data demonstrating that active transcription regulates levels of genomic methylation. We identified a novel RNA arising from the CEBPA gene locus critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extended the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1-RNA interactions and suggest strategies for gene selective demethylation of therapeutic targets in disease.

The gene mtsl, which is expressed specifically in metastatic cells, was isolated by molecular cloning coupled with differential DNA reassociation. Transcription of mtsl was found not only in tumor cells, but also in normal cells; homologous RNA was detected only in spleen, thymus, bone marrow, and blood lymphocytes. DNA sequencing of mtsl revealed an open reading frame containing information for a peptide of 101 amino acids, and the amino acid sequence suggested that the mtsl protein was identical to the previously isolated Ca2+-binding mouse protein (Jackson-Grusby et al. 1987; Goto et al. 1988). Thus, the mtsl protein is a member of the calcium-modulated protein family, and our data indicate that mtsl is involved in regulating the metastatic behavior of tumor cells.

Key Points• Human hematopoietic cells develop within human iPSCderived teratomas in immunodeficient mice.• Co-transplantation of OP9 stromal cells along with human iPSCs increases hematopoietic specification within teratomas.