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Novel insights into the downstream pathways and targets controlled by transcription factors CREM in the testis.

Kosir R, Juvan P, Perse M, Budefeld T, Majdic G, Fink M, Sassone-Corsi P, Rozman D - PLoS ONE (2012)

Bottom Line: Among them are 101 genes associated with spermatogenesis 41 of which are bound by CREM and are deregulated in Crem KO testis.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

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.

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Data comparison.Differentially expressed (DE) genes were compared to the Crem ChIP-seq dataset from Martianov et al[9] from 2010 (dataset of genes that are bound by Crem in testis), the Affymetrix MG U 74A dataset from Beissbarth et al[8] from 2003 (dataset of DE genes between WT and KO mice testis) and the TFCat dataset from Fulton et al[38] (a hand curated database of transcriptional factors). A – DE genes that are bound by Crem; B – DE genes that are transcriptional factors; C – DE genes that are transcriptional factors bound by Crem; D, E and F are genes common to both analysis using Affymetrix microarrays. Numbers represent the number of genes in each dataset or the number of common genes between comparisons.
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pone-0031798-g002: Data comparison.Differentially expressed (DE) genes were compared to the Crem ChIP-seq dataset from Martianov et al[9] from 2010 (dataset of genes that are bound by Crem in testis), the Affymetrix MG U 74A dataset from Beissbarth et al[8] from 2003 (dataset of DE genes between WT and KO mice testis) and the TFCat dataset from Fulton et al[38] (a hand curated database of transcriptional factors). A – DE genes that are bound by Crem; B – DE genes that are transcriptional factors; C – DE genes that are transcriptional factors bound by Crem; D, E and F are genes common to both analysis using Affymetrix microarrays. Numbers represent the number of genes in each dataset or the number of common genes between comparisons.

Mentions: DE genes from our dataset were compared to TFCat transcription factor database [38] and to the CREM ChIP-seq database [9] using Venn and Euler diagrams. The numbers of genes present in each comparison as well as the number of all genes in each dataset are shown in Figure 2. Comparisons (A, B and C, Figure 2) enabled to determine which of the differentially expressed genes from our dataset are: (A) bound by the CREM protein (comparison A, Figure 2), (B) are transcriptional factors (comparison B, Figure 2) or (C) are transcriptional factors bound by CREM (comparison C, Figure 2). Comparisons D, E and F were used to evaluate the overlap between our dataset and the dataset from Beissbarth et al[8]. A more detailed overview of all comparisons between the four datasets is presented in Euler diagrams in Figure 3. We show that the absence of Crem deregulates a large number of genes in KO testis, however not all are direct targets of the CREM protein. Only 1607 (34%) fall into the cross section between our and ChIP-seq data (Figure 3, Table S4), while the rest (3099) are probably affected due to secondary effects of CREM absence. A comparison with the TFCat database [38] (Figure 3B and 3C) showed that 85 DE genes are transcription factors and are according to the analysis of GO terms (and KEGG pathways) involved in cell differentiation, development and spermatogenesis. Forty of these transcription factors are also bound by CREM (Figure 3C, Table S5). These transcription factors can explain the secondary effects of the CREM absence.


Novel insights into the downstream pathways and targets controlled by transcription factors CREM in the testis.

Kosir R, Juvan P, Perse M, Budefeld T, Majdic G, Fink M, Sassone-Corsi P, Rozman D - PLoS ONE (2012)

Data comparison.Differentially expressed (DE) genes were compared to the Crem ChIP-seq dataset from Martianov et al[9] from 2010 (dataset of genes that are bound by Crem in testis), the Affymetrix MG U 74A dataset from Beissbarth et al[8] from 2003 (dataset of DE genes between WT and KO mice testis) and the TFCat dataset from Fulton et al[38] (a hand curated database of transcriptional factors). A – DE genes that are bound by Crem; B – DE genes that are transcriptional factors; C – DE genes that are transcriptional factors bound by Crem; D, E and F are genes common to both analysis using Affymetrix microarrays. Numbers represent the number of genes in each dataset or the number of common genes between comparisons.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285179&req=5

pone-0031798-g002: Data comparison.Differentially expressed (DE) genes were compared to the Crem ChIP-seq dataset from Martianov et al[9] from 2010 (dataset of genes that are bound by Crem in testis), the Affymetrix MG U 74A dataset from Beissbarth et al[8] from 2003 (dataset of DE genes between WT and KO mice testis) and the TFCat dataset from Fulton et al[38] (a hand curated database of transcriptional factors). A – DE genes that are bound by Crem; B – DE genes that are transcriptional factors; C – DE genes that are transcriptional factors bound by Crem; D, E and F are genes common to both analysis using Affymetrix microarrays. Numbers represent the number of genes in each dataset or the number of common genes between comparisons.
Mentions: DE genes from our dataset were compared to TFCat transcription factor database [38] and to the CREM ChIP-seq database [9] using Venn and Euler diagrams. The numbers of genes present in each comparison as well as the number of all genes in each dataset are shown in Figure 2. Comparisons (A, B and C, Figure 2) enabled to determine which of the differentially expressed genes from our dataset are: (A) bound by the CREM protein (comparison A, Figure 2), (B) are transcriptional factors (comparison B, Figure 2) or (C) are transcriptional factors bound by CREM (comparison C, Figure 2). Comparisons D, E and F were used to evaluate the overlap between our dataset and the dataset from Beissbarth et al[8]. A more detailed overview of all comparisons between the four datasets is presented in Euler diagrams in Figure 3. We show that the absence of Crem deregulates a large number of genes in KO testis, however not all are direct targets of the CREM protein. Only 1607 (34%) fall into the cross section between our and ChIP-seq data (Figure 3, Table S4), while the rest (3099) are probably affected due to secondary effects of CREM absence. A comparison with the TFCat database [38] (Figure 3B and 3C) showed that 85 DE genes are transcription factors and are according to the analysis of GO terms (and KEGG pathways) involved in cell differentiation, development and spermatogenesis. Forty of these transcription factors are also bound by CREM (Figure 3C, Table S5). These transcription factors can explain the secondary effects of the CREM absence.

Bottom Line: Among them are 101 genes associated with spermatogenesis 41 of which are bound by CREM and are deregulated in Crem KO testis.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

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.

Show MeSH
Related in: MedlinePlus