The Sm protein methyltransferase PRMT5 is not required for primordial germ cell specification in mice.

PRMT5 is a type II protein arginine methyltransferase with roles in stem cell biology, reprograming, cancer and neurogenesis. During embryogenesis in the mouse, it was hypothesized that PRMT5 functions with the master germline determinant BLIMP1 to promote primordial germ cell (PGC) specification. Using a Blimp1-Cre germline conditional knockout, we discovered that Prmt5 has no major role in murine germline specification, or the first global epigenetic reprograming event involving depletion of cytosine methylation from DNA and histone H3 lysine 9 dimethylation from chromatin. Instead, we discovered that PRMT5 functions at the conclusion of PGC reprograming I to promote proliferation, survival and expression of the gonadal germline program as marked by MVH. We show that PRMT5 regulates gene expression by promoting methylation of the Sm spliceosomal proteins and significantly altering the spliced repertoire of RNAs in mammalian embryonic cells and primordial cells.

Comparison of Mirena and Liletta levonorgestrel intrauterine devices for the treatment of endometrial intraepithelial neoplasia and grade 1 endometrioid endometrial cancer.

Objective: Current standard nonsurgical management of endometrial intraepithelial neoplasia (EIN) and grade 1 endometrioid endometrial cancer (g1EEC) is the Mirena levonorgestrel intrauterine device (M-IUD). This retrospective study was designed primarily to determine noninferiority of the Liletta IUD (L-IUD) for pathologic regression of EIN and g1EEC compared to the M-IUD at 6 months of continuous use. Secondary objectives include to determine noninferiority as above at 3, 9, and 12 months of continuous use and to identify factors including DNA mismatch repair (MMR) status associated with pathologic regression after LNG-IUD use. Methods: A retrospective observational study was performed with patients treated for EIN or g1EEC and managed continuously with M- or L-IUD. Patients with recent (within 6 months) or concurrent progesterone use were excluded. For the EIN group, the noninferiority margin of odds ratio was predetermined to be 0.58, and for the g1EEC group it was 0.64. Results: 62 patients from an academic center and a safety-net hospital were identified with continuous M-IUD (n = 44) or L-IUD (n = 18) use for EIN or g1EEC. 85% of patients treated with L-IUD were from a safety-net hospital, which had 63% with public insurance. At 3/6/9 months, 54/71/73% of patients with M-IUD and 80/83/100% with L-IUD had pathologic regression of EIN (95% confidence interval of estimated odds ratio 1.00-2.07/0.84-2.03/0.69-2.10). Lifetime smoking status, not MMR status, was significantly associated with pathologic regression. Conclusions: L-IUD is an effective fertility-sparing treatment for EIN. L-IUD is noninferior to M-IUD for pathologic regression of EIN after 3,6, and 9 months. Further larger studies are warranted to validate findings in EIN and g1EEC.