Trim66’s paternal deficiency causes intrauterine overgrowth

The tripartite motif-containing protein 66 (TRIM66, also known as TIF1-delta) is a PHD-Bromo containing protein primarily expressed in post-meiotic male germ cells known as spermatids. Biophysical assays showed that TRIM66 PHD-Bromo domain binds to H3 N-terminus only when lysine 4 is unmethylated. We addressed TRIM66’s role in reproduction by loss-of-function genetics in the mouse. Males homozygous for Trim66-null mutations produced functional spermatozoa. Round spermatids lacking TRIM66 upregulated a network of genes involved in histone acetylation and H3K4 methylation. Profiling of H3K4me3 patterns in the sperm produced by Trim66 -null mutant showed minor alterations below statistical significance. Unexpectedly, Trim66 -null males, but not females, sired pups overweight at birth, hence revealing that Trim66 mutations cause a paternal effect phenotype.