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Differential microRNA expression in the ovaries of high and low prolificacy pregnant sows from an Iberian x Meishan F2 intercross

ABSTRACT: Prolificacy related traits are of great economical interest in the pig industry. microRNAs (miRNAs) are post-transcriptional regulators of gene expression important for reproductive processes. In pigs, the roles of ovarian miRNAs during gestation remain unknown although the ovaries are essential during gestation. It has been hypothesised that ovarian miRNAs could participate during the porcine gestation and, moreover, they could influence the prolificacy levels of sows. The miRNA expression profile was compared in the ovaries of pregnant Iberian x Meishan F2 sows displaying extreme phenotypes regarding prolificacy levels defined as the number of embryos (NE) attached to the uterus at 30-32 days of gestation. miR-146a-5p and miR-142-3p were differentially expressed between high (NE≥13) and low (NE≤11) prolificacy sows. In silico functional analyses of the predicted mRNA targets for these miRNAs revealed that miR-146a-5p targets were mainly involved in the immune system response important for the establishment of the maternal-foetal tolerance, implantation and maintenance of pregnancy. On the other hand, miR-142-3p targets participated in different biological processes that would contribute to the homeostasis maintenance to ensure a correct functional development of the ovaries. miRNAs associated with prolificacy levels could regulate negatively, by a novel post-transcriptional mechanism, their predicted mRNA targets, PPM1K, TLR1 and CPEB2 which have been reported as differentially expressed in the ovaries of pregnant sows regarding the prolificacy levels. Furthermore, among predicted mRNA targets for miRNAs associated with prolificacy, four genes, differentially expressed in the ovaries of pregnant sows regarding prolificacy levels, (LRRK1, BAT1, CPEB2, CCL8) are proposed to be good candidate genes for litter size due to their location within confidence intervals for prolificacy QTL described previously. Overall, it is suggested that the up-regulation of miR-146a-5p and miR-142-3p in the ovaries of pregnant sows could help in the establishment of a uterine environment, which would favor the embryonic development.

ORGANISM(S): Sus scrofa

PROVIDER: GSE41068 | GEO | 2012/12/01

SECONDARY ACCESSION(S): PRJNA175667

REPOSITORIES: GEO

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Project description:Prolificacy related traits are of great economical interest in the pig industry. microRNAs (miRNAs) are post-transcriptional regulators of gene expression important for reproductive processes. In pigs, the roles of ovarian miRNAs during gestation remain unknown although the ovaries are essential during gestation. It has been hypothesised that ovarian miRNAs could participate during the porcine gestation and, moreover, they could influence the prolificacy levels of sows. The miRNA expression profile was compared in the ovaries of pregnant Iberian x Meishan F2 sows displaying extreme phenotypes regarding prolificacy levels defined as the number of embryos (NE) attached to the uterus at 30-32 days of gestation. miR-146a-5p and miR-142-3p were differentially expressed between high (NEM-bM-^IM-%13) and low (NEM-bM-^IM-$11) prolificacy sows. In silico functional analyses of the predicted mRNA targets for these miRNAs revealed that miR-146a-5p targets were mainly involved in the immune system response important for the establishment of the maternal-foetal tolerance, implantation and maintenance of pregnancy. On the other hand, miR-142-3p targets participated in different biological processes that would contribute to the homeostasis maintenance to ensure a correct functional development of the ovaries. miRNAs associated with prolificacy levels could regulate negatively, by a novel post-transcriptional mechanism, their predicted mRNA targets, PPM1K, TLR1 and CPEB2 which have been reported as differentially expressed in the ovaries of pregnant sows regarding the prolificacy levels. Furthermore, among predicted mRNA targets for miRNAs associated with prolificacy, four genes, differentially expressed in the ovaries of pregnant sows regarding prolificacy levels, (LRRK1, BAT1, CPEB2, CCL8) are proposed to be good candidate genes for litter size due to their location within confidence intervals for prolificacy QTL described previously. Overall, it is suggested that the up-regulation of miR-146a-5p and miR-142-3p in the ovaries of pregnant sows could help in the establishment of a uterine environment, which would favor the embryonic development. Total RNA was isolated from uterus of Iberian x Meishan F2 pregnant sows divided into two groups: High prolificacy sows (n=3) and Low prolificacy sows (n=3). RNA was labeled with the Cy3-like Hy3M-bM-^DM-" dye, mixed with a pool of RNA from the six samples labeled with the Cy5-like Hy5M-bM-^DM-" dye, and hybridized to two-color miRCURYM-bM-^DM-" arrays from ExiqonM-BM-..

Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.

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Differential microRNA expression in the ovaries of high and low prolificacy pregnant sows from an Iberian x Meishan F2 intercross

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