QSER1 protects DNA methylation valleys from de novo methylation

DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to regulate the methylation landscape remains a central question. Using a knockin DNA methylation reporter, we performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene, QSER1, which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNAmethylation valleys (or canyons). We further demonstrate genetic and biochemical interactions of QSER1 and TET1, supporting their cooperation to safeguard transcriptional and developmental programs from DNMT3-mediated de novo methylation.

Automated summary

The previously unknown gene QSER1 plays a crucial role in regulating the methylation landscape, safeguarding bivalent promoters and poised enhancers of developmental genes, especially those in DNA methylation valleys. The genetic and biochemical interactions of QSER1 and TET1 support their cooperation in protecting transcriptional and developmental programs from de novo methylation mediated by DNMT3.