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P7 TAF4b-dependent transcription and ist relevance for male fertility in humans

Sperm morphogenesis is largely based on translationally repressed stored mRNAs in mammals, as well as in the model organism Drosophila. In Drosophila, five testis-specific TATA-box binding protein (TBP)-associated factors (tTAFs) have been identified which control activation of differentiation-relevant genes. All target genes known so far are solely transcribed in a single cell type, namely spermatocytes, and kept in a repressive status in all other cell types - presumably by polycomb complexes

There is evidence that tTAFs not only act within the transcription initiation complex, but in addition counteract polycomb in a way that polycomb is removed from the sperm differentiation genes and transcription can take place. Importantly, with TAF4b, a first homologue of one of these tTAFs has been found in human. Recently, expression of TAF4b was also observed in the male germ line of mice, namely in spermatogonia and early spermatids, explaining sterility of knock-out mice. In mammals, sperm differentiation genes, e.g. transition proteins and protamines, are transcribed at the round spermatid stage, but translated in later stages. The transcriptome of early spermatids has been analyzed in mice. Aims of the present study: 1) To clarify whether TAF4b is required for transcription of translationally repressed mRNAs in mammals applying ChIP with candidate target genes, e.g. protamines; 2) To identify TAF4b target genes in early spermatids using genome-wide ChIP. Subsequently, individual targets will be verified; 3) To analyze which bromodomain proteins and components of the polycomb-repressive complex characterize early spermatids; 4) To analyze subfertile men with post-meiotic defects with a special focus on bromodomain proteins, polycomb, TAF4b and identified targets.