STRUCTURE OF THE IMPRINTED MOUSE SNRPN GENE AND ESTABLISHMENT OF ITS PARENTAL-SPECIFIC METHYLATION PATTERN

The mouse Snrpn gene encodes the Smn protein, which is involved in RNA splicing, The gene maps to a region in the central part of chromosome 7 that is syntenic to the Prader-Willi/Angelman syndromes (PWS-AS) re gion on human chromosome 15q11-q13. The mouse gene, like its human cou nterpart, is imprinted and paternally expressed, primarily in brain an d heart, We provide here a detailed description of the structural feat ures and differential methylation pattern of the gene, We have identif ied a maternally methylated region at the 5' end (DMR1), which correla tes inversely with the Snrpn paternal expression, We also describe a r egion at the 3' end of the gene (DMR2) that is preferentially methylat ed on the paternal allele, Analysis of Snrpn mRNA levels in a methylas e-deficient mouse embryo revealed that maternal methylation of DMR1 ma y play a role in silencing the maternal allele, Yet both regions, DMR1 and DMR2, inherit the parental-specific methylation profile from the gametes, This methylation pattern is erased in 12.5-days postcoitum (d pc) primordial germ cells and reestablished during gametogenesis. DMR1 is remethylated during oogenesis, whereas DMR2 is remethylated during spermatogenesis. Once established, these methylation patterns are tra nsmitted to the embryo and maintained, protected from methylation chan ges during embryogenesis and cell differentiation. Transfections of DM R1 and DMR2 into embryonic stem cells and injection into pronuclei of fertilized eggs reveal that embryonic cells lack the capacity to estab lish anew the differential methylation pattern of Snrpn, That all PWS patients lack DMR1, together with the overall high resemblance of the mouse gene to the human SNRPN, offers an excellent experimental tool t o study the regional control of this imprinted chromosomal domain.