Urzúa et al. BMC Genomics 2010, 11(Suppl 5):S1 http://www.biomedcentral.com/1471-2164/11/S5/S1 no association was detected between OTF and LS in our data. It may be hypothesized that the damage caused to the epithelial surface during a multiple-ovulation event can be repaired during subsequent pregnancy and lacta- tion, a period without cycling and ovulations. Additional file 4 shows that 11 of the 76 OTF–/NL+ genes are implicated either in normal or pathological ovarian processes. RNA binding was the predominant GO term in the 76-genes list reaching 22 genes. RNA binding proteins have been implicated in mammalian germ cell development [33]. The genes Cpsf6, Ddx17, Fubp1, Hnrpa2b1, Rbm25, Rbm39, Sfrs2 and Sfrs6 share GO terms (RNA binding, mRNA processing) and a rela- tionship with normal ovarian function or ovarian-related disease. Some genes not related to RNA metabolism but linked to ovarian function were correlated to OTF–/NL +. These include Ece1, expressed in steroidogenic and follicular endothelial ovarian cells in a parallel fashion to corpus luteum maturation [34], and the genes Arnt and Nfat5 that regulate the activity of vascular endothelial growth factor (VEGF), an important angiogenesis modu- lator in normal and pathological conditions including ovarian malignancies [35]. Arnt (alias HIF-beta) binds the hypoxia inducible factor-1 alpha (HIF-1alpha) to form a heterodimer that recognizes the VEGF promoter [36]. Arnt can alternatively bind the aryl hydrocarbon receptor (AHR) forming an AHR/ARNT complex which controls FSH and LH concentrations in response to AHR ligands [37]. Furthermore, down-regulation of Nfat5 (nuclear factor of activated T-cells 5) parallels a decrease in VEGF’s receptor VEGFR1 and an increase in VEGFR2 in hemangioma endothelial cells [38]. Additional regulators of VEGF’s function in the OTF–/NL+ list were the genes Sfrs6 and Rbm39. The splicing factor Sfrs6 (alias SRp55) upregulates the anti- angiogenic VEGF isoform, an alternative splicing pro- duct involving the 8th exon of VEGF’s pre-mRNA [39]. Since Sfrs6 displayed an OTF–/NL+ correlation pattern, this is suggestive of an anti-angiogenic condition asso- ciated to multiparity and low ovarian tumor incidence. VEGF levels itself were neither differentially expressed nor correlated to any phenotype in this study, but the CDC-like kinase 1 (Clk1), which mediates Sfrs6 activity on anti-angiogenic VEGF levels [39], was also part of the OTF–/NL+ list (see Additional file 3 “OTF&NL_- correlated_transcripts.xls”). In addition, Rbm39 (alias CAPERalpha) is able to alter the VEGF-121/VEGF-189 ratio in breast cancer cells [40]. Rbm39 was originally described as an ERa/b transcriptional coactivator [41]. Analogous role has been reported for the DEAD-box RNA helicases Ddx17 (alias p72) and Ddx5 (alias p68). [42]. Ddx17 was in a OTF–/NL+ fashion while Ddx5 plus Ddx26b, Ddx3x and Ddx42 were present in the overall 400-genes list. Page 7 of 11 Regarding the OTF+/NL– correlated genes, the predo- minant GO term was “protein folding” including Dnajb1, Hsp90aa1 and P4hb (see Additional file 4 and Figure 2). Dnajb1 is a member of the Hsp40 co-chaper- one protein family of which its Drosophyla homolog participates in oogenesis [43]. Related Hsp-40 genes Dnaja1, Dnajb6, and Dnajc7 were present in the overall 400-genes list. Hsp90aa1 expression is up-regulated in ovarian endometriosis [44] while P4hb is involved in post-translational modifications of procollagen synthesis [45]. Other transcripts with OTF+/NL– correlation were Spin1 (Spindlin 1), a protein that associates to CPEB, a RNA-binding protein implicated in polyadenylation dur- ing meiotic progression in oocytes [46], and the tran- scription factor Cited1, reported as a FSH regulated gene in human granulosa cells [47]. All the five phenotypes studied are complex and many causal effects are certainly involved. It is quite possible that a large fraction of correlated transcripts may be simply bystanders but not lie behind the measured phe- notype. Of the 56 genes listed in Additional file 4, seventeen are classified under the GO term “regulation of transcription”. These may be considered “master genes”, i.e. encoding for protein products that somehow interact with DNA regulatory sequences or transcrip- tional multiprotein complexes thus modulating the tran- scriptional activity of downstream genes. Among the OTF–/NL+ correlated genes with roles in regulation of transcription, we identified Fubp1, Rbm39 and Arnt which are directly linked to ovarian biology or disease (see Additional file 4). Fubp1 encodes a ssDNA binding protein that activates the “far upstream element” of c- myc thus stimulating its transcription. Interestingly, pro- moter regions of the OTF–/NL+ genes Ccnl1, Clk4, Coq10a, Ddx17, Ict1, Zc3h11a and Zc3h7a were found to contain binding sites for Arnt (data not shown). In addition, the genes Hnrpdl, Sltm, Tardbp, Ccnl1, Ccnl2, Dmtf1, Mll3, Mycbp2, Nfat5, Suv420h2, and 1810007M14 display diverse roles in cancer and devel- opmental processes (see Additional file 4 for Refer- ences). Special mention deserve the c-myc binding protein Mycbp2, the gene Sltm, which has been described as modulator of estrogen induced transcrip- tion, and the cyclins Ccnl1 and Ccnl2 which are tran- scriptional regulators of pre-mRNA splicing. Phenotypic information obtained from independent studies on animals need to be integrated in order to reliably compare results across different mice colonies and laboratory set-ups. The sources of phenotypic data used in the present study are metadatabases in which uniformity criteria and manual curation has been imposed on assembled records. The Mouse Tumor Biol- ogy Database (MTB) contains both spontaneous and induced tumor information for over 50 inbred strains,