Elucidating the biological function of UHRF2 in mammals – METHU2

DNA methylation of CpGs is catalyzed by enzymes of the DNA methyltransferase (DNMT) family and plays major roles in gene regulation and genome integrity in mammals. DNMT1 copies DNA methylation after replication to ensure inheritance through cell divisions and is recruited to chromatin by its cofactor UHRF1. Vertebrate genomes encode a paralog of Uhrf1, named Uhrf2, whose potential roles in DNA methylation remain enigmatic. We have obtained solid preliminary data showing that Uhrf2 is specifically required for maintenance DNA methylation of transposable elements (TEs) in germ cells and fertility in the mouse. Building on these exciting preliminary data, we propose to explore the epigenetic roles of Uhrf2 in mammalian germ cells in 4 aims: 1) Validate the role of Uhrf2 in DNA methylation at the genome-wide level in mouse germ cells; 2) Investigate the biological importance of Uhrf2 in mouse germ cells; 3) Elucidate the molecular mechanisms of UHRF2 targeting to TEs in germ cells; 4) Investigate if UHRF2 mutations are associated with infertility in humans. The project is led by an interdisciplinary consortium of 4 laboratories bringing together complementary expertise and a range of advanced technologies in DNA methylation, germ cell biology and human genetics. The project addresses key unsolved biological questions; it will provide novel functions for the enigmatic Uhrf2 gene and novel findings on the epigenetic control of germ cell development in mammals with potential implications for human infertility.