The Dot1L histone H3 methyltransferase is essential for early Mammalian development and hematopoiesis (138.15)

Histone methylation of H3 is catalyzed by at least two families of proteins, the PRMT family and the SET family. Recent studies have found a new histone H3 methyltransferase without a SET domain named Dot1L (disrupter of telomere silencing 1-like). To investigate the function of Dot1L, a Dot1L deficient mouse line was generated by injection of murine embryonic stem (ES) cells containing a gene trap into C57BL/6 female blastocysts (clone #RRR032; Bay Genomics, San Francisco, CA). Fibroblasts from Dot1L-homozygous mutant embryos were completely defective in their ability to methylate lysine 79 of histone H3. All knockout embryos died by embryonic day 13. The knockout embryos showed significant reductions in blood and blood vessel formation. Further, colony assays revealed a defect primarily in early erythropoiesis. The early erythroid precursor cells were defective in their ability to respond to erythropoietin, and the cells were more susceptible to early apoptosis after stimulation. We conclude that Dot1L plays an important role in early hematopoiesis, primarily affecting early erythroid precursor cells.