title: Novel insights into the downstream pathways and targets controlled by transcription factors CREM in the testis.
abstract: The essential role of the Crem gene in normal sperm development is widely accepted and is confirmed by azoospermia in male mice lacking the Crem gene. The exact number of genes affected by Crem absence is not known, however a large difference has been observed recently between the estimated number of differentially expressed genes found in Crem knock-out (KO) mice compared to the number of gene loci bound by CREM. We therefore re-examined global gene expression in male mice lacking the Crem gene using whole genome transcriptome analysis with Affymetrix microarrays and compared the lists of differentially expressed genes from Crem-/- mice to a dataset of genes where binding of CREM was determined by Chip-seq. We determined the global effect of CREM on spermatogenesis as well as distinguished between primary and secondary effects of the CREM absence. We demonstrated that the absence of Crem deregulates over 4700 genes in KO testis. Among them are 101 genes associated with spermatogenesis 41 of which are bound by CREM and are deregulated in Crem KO testis. Absence of several of these genes in mouse models has proven their importance for normal spermatogenesis and male fertility. Our study showed that the absence of Crem plays a more important role on different aspects of spermatogenesis as estimated previously, with its impact ranging from apoptosis induction to deregulation of major circadian clock genes, steroidogenesis and the cell-cell junction dynamics. Several new genes important for normal spermatogenesis and fertility are down-regulated in KO testis and are therefore possible novel targets of CREM.
authors.affiliation: Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Rok
authors.initials: R
authors.lastname: Kosir
authors.forename: Peter
authors.initials: P
authors.lastname: Juvan
authors.forename: Martina
authors.initials: M
authors.lastname: Perse
authors.forename: Tomaz
authors.initials: T
authors.lastname: Budefeld
authors.forename: Gregor
authors.initials: G
authors.lastname: Majdic
authors.forename: Martina
authors.initials: M
authors.lastname: Fink
authors.forename: Paolo
authors.initials: P
authors.lastname: Sassone-Corsi
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
mesh_terms: D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D051786:Cyclic AMP Response Element Modulator / Q000096:biosynthesis / Q000502:physiology*; D005306:Fertilization; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006720:Homozygote; D008297:Male; D008550:Melatonin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D013087:Spermatids / Q000378:metabolism; D013091:Spermatogenesis; D013094:Spermatozoa / Q000378:metabolism; D013737:Testis / Q000378:metabolism*
chemical_list: D051786:Cyclic AMP Response Element Modulator; D008550:Melatonin