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Sex Determines the Expression Level of One Third of the Actively Expressed Genes in Bovine Blastocysts

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Sex Determines the Expression Level of One Third of the Actively Expressed Genes in Bovine Blastocysts Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts P. Bermejo-Alvareza, D. Rizosa, D. Rathb, P. Lonerganc, and A. Gutierrez-Adana,1 aDepartamento de Reproducción Animal y Conservación de Recursos Zoogenéticos, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid 28040, Spain; bInstitute of Farm Animal Genetics, Friedrich-Loeffer-Institut, 31535 Neustadt-Mariensee, Germany; and cSchool of Agriculture, Food Science, and Veterinary Medicine, University College Dublin, Dublin 4, Ireland Edited by George Seidel, Colorado State University, and approved January 6, 2010 (received for review December 3, 2009) Although genetically identical for autosomal Chrs (Chr), male and inactivation process and be expressed biallelically. This situation is female preimplantation embryos could display sex-specific transcrip- especially common during preimplantation development, when X tional regulation. To illustrate sex-specific differences at the mRNA inactivation is a reversible dynamic process (11) and may lead to an level, we compared gene-expression patterns between male and up-regulation of X-linked genes in female embryos (2, 3). On the female blastocysts by DNA microarray comparison of nine groups of other hand, male embryos only contain the maternally inherited X- 60 bovine in vitro-produced blastocysts of each sex. Almost one-third Chr; thus, an X-linked gene up-regulation in females may also occur of the transcripts detected showed sexual dimorphism (2,921 tran- as a result of an imprinting mechanism leading to a total or partial scripts; false-discovery rate, P < 0.05), suggesting that in the absence maternal allele transcriptional repression (11). of hormonal influences, the sex Chrs impose an extensive transcrip- Global gene expression analyses in preimplantation embryos tional regulation upon autosomal genes. Six genes were analyzed by are scarce, mainly because of the technical difficulties in obtaining qPCR in in vivo-derived embryos, which displayed similar sexual the necessary large number of embryos per group. To our dimorphism. Ontology analysis suggested a higher global transcrip- knowledge, there is only one report on global differences in gene tional level in females and a more active protein metabolism in males. expression in male and female blastocysts, which used a transgenic A gene homolog to an X-linked gene involved in network interactions mouse model to obtain the biological material (12). Sex-sorted during spliceosome assembly was found in the Y-Chr. Most of the semen constitutes a powerful tool for these studies, as it can X-linked-expressed transcripts (88.5%) were up-regulated in females, provide a large number of embryos of known sex in species with a but most of them (70%) exhibited fold-changes lower than 1.6, sug- longer preimplantation period, such as bovine. In this study, we gesting that X-Chr inactivation is partially achieved at the blastocyst aimed to analyze preimplantation sexual dimorphism mecha- stage. Almost half of the transcripts up-regulated in female embryos nisms at the transcriptional level by microarray gene-expression exhibiting more than 1.6-fold change were present in the X-Chr and profiling of bovine blastocysts produced in vitro. We also con- eight of them were selected to determine a putative paternal imprint- firmed the findings for in vivo-derived embryos, performed ing by gene expression comparison with parthenogenetic embryos. BEX CAPN6 BEX2 SRPX2 UBE2A ontology analysis, reported a previously unreported Y-linked Five ( , , , ,and ) exhibited a higher transcript, and determined the putative imprinting of eight X- expression in females than in parthenotes, suggesting that they are linked genes up-regulated in female embryos. predominantly expressed by the paternal inherited X-Chr and that imprinting may increase the transcriptional skew caused by double Results X-Chr dosage. Microarray Overall Results and Validation. More than 1,000 blasto- cysts of known sex were produced in 12 independent experiments. gender | preimplantation | microarray | imprinting | X-inactivation The global gene-expression pattern of nine pools each of male and female bovine blastocysts (n = 60 blastocysts per pool) was n mammals, sexual dimorphism is mostly attributable to sex- compared with the GeneChip Bovine Genome Array. A total of Irelated hormonal differences in fetal and adult tissues; however, 9,322 transcripts were present at the blastocyst stage. The total this may not be the sole determinant. Before gonad differentiation number of transcripts differing between male and female embryos occurs, male and female preimplantation embryos display phe- is listed in Table 1 and Table S1. Hierarchical distribution clearly notypic differences that can only be attributed to the different sex grouped the samples according to the sex, irrespective of the bull Chr dosage. Although male and female blastocysts carry the same used (Fig. 1A and Fig. S1). Therefore, statistical analysis was autosomal DNA, gender-specific transcription or translation performed by grouping the data from the nine arrays of each sex occurs. At these early stages, sex Chrs modulate the genome obtained from samples of the three different bulls. Principal machinery leading to differences in epigenetic status (1) and component analysis demonstrated that the sexes clearly separated expression level of both X-linked (2, 3) and autosomal genes (1, 4, and, interestingly, within each sex, the three replicates from each 5). These molecular events are reflected in phenotypic differences bull clustered together (Fig. 1A and Fig. S1). The large sample reported under some culture conditions, including differences in size obtained after grouping the data allowed us to detect small speed of embryo development, survival after vitrification, cell number at the blastocyst stage, and metabolism. In particular, glucose metabolism is thought to differ between male and female Author contributions: D. Rizos, P.L., and A.G.-A. designed research; P.B.-A. performed embryos (6), which may lead to a skewing in sex ratio because of research; D. Rizos, D. Rath, and P.L. contributed new reagents/analytic tools; P.B.-A., D. preferential loss of embryos of one sex occurring both in vitro (7, 8) Rath, and A.G.-A. analyzed data; and P.B.-A., P.L., and A.G.-A. wrote the paper. and in vivo (9, 10). The authors declare no conflict of interest. In a genomic context, transcriptional analyses during preim- This article is a PNAS Direct Submission. plantation development provide a useful tool to study hormone- Data deposition: Raw data from microarray experiments was submitted to the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo). The platform ID is independent sexual dimorphism phenomena. Both sex Chrs encode GPL2112. The accession ID for the set of experiments described is GSE17921. A new transcripts, which not only can have a direct effect upon phenotypic 1382 pb cDNA was identified YZRSR2 (GQ426330). G6PD HPRT 1 differences (i.e., and ) but also can modulate the To whom correspondence should be addressed. E-mail: [email protected]. expression of autosomal genes (1). In adult tissues, one of the X- This article contains supporting information online at www.pnas.org/cgi/content/full/ Chrs is inactivated, but some genes can escape from the X-Chr 0913843107/DCSupplemental. 3394–3399 | PNAS | February 23, 2010 | vol. 107 | no. 8 www.pnas.org/cgi/doi/10.1073/pnas.0913843107 Downloaded by guest on September 25, 2021 Table 1. Results of microarray analysis of transcripts differentially expressed between male (M) and female (F) bovine blastocysts Comparison Multiple Up-regulated genes Up-regulated genes Fold-changes > 2 (# of samples) test correction in females in males Total female/male F vs. M(9 vs. 9) None 1,667 2,089 3,745 53/2 FDRP < 0.05 1,330 1,591 2,921 53/2 FDR P < 0.01 897 914 1,811 53/2 Bonferroni P < 0.05 290 92 382 45/2 Statistical analysis from comparison of nine pools each of male and female embryos. absolute differences and after false-discovery rate (FDR) assess- Array validation by quantitative PCR (qPCR) was performed in ment of significance (P < 0.05) correction was applied to reduce embryos produced with unsorted sperm to confirm that observed the number of false-positives, a total of 2,921 transcripts differed sex-related transcript differences were not artifacts of the use of between male and female blastocysts, which constitutes almost sorted sperm. Eight X-linked genes (BEX1, CAPN6, FMR1NB, one-third of the transcripts actively expressed. The fold-change SAT1, BEX2, X24112, SRPX2, and UBE2A), one transcript puta- for most of the transcripts was below 2. For 55 transcripts, the tively present on both sex Chrs (Y2467), a previously unreported fold-change was higher than 2, 53 of which were up-regulated in gene located on the Y-Chr (YZRSR2), and four autosomal genes females. Transcripts up-regulated (with the higher values) in male (GSTM3, PGRMC1, LAMA1, and DNMT3A), together with two and female bovine blastocysts are listed in Tables S2 and S3.A Y-linked genes with an X-linked homolog not present on the array higher level of fold-changes of up-regulated transcripts was found were analyzed. Fold-change values obtained by qPCR were very in female than in male embryos. similar to those obtained in the array (Table 2). A 20 B 18 Expressed 16 Upregulated in male 14 Upregulated in female 12 10 8 % of genes of % 6 4 2 0 1 2 3 4 5 6 7 8 9 1011121314151617181920212223242526272829X Y Chromosome C 60 >2 50 1.66-2 40 1.33-1.66 30 1-1.33 20 No differences genes % X-linked 10 <1 0 >2 1.66-2 1.33-1.66 1-1.33 Fold change Fig. 1. Comparison of male and female bovine blastocysts. (A) Hierarchical clustering of the 382 differentially expressed transcripts (Bonferroni correction) between male and female bovine blastocysts, comparing three different bulls and the three pools of embryos derived from Y- and X-sorted semen from each bull.
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