Project description:An important question for the use of the mouse as a model for studying human disease is the degree of functional conservation of genetic control pathways from human to mouse. The human placenta and mouse placenta show structural similarities but there has been no systematic attempt to assess their molecular similarities or differences. We built a comprehensive database of protein and microarray data for the highly vascular exchange region micro-dissected from the human and mouse placenta near-term. Abnormalities in this region are associated with two of the most common and serious complications of human pregnancy, maternal preeclampsia (PE) and fetal intrauterine growth restriction (IUGR), each disorder affecting ~5% of all pregnancies. To compare the gene expression patterns in the vascular exchange regions of the human (villus tree) and mouse (labyrinth) placenta. Keywords: comparison
Project description:An important question for the use of the mouse as a model for studying human disease is the degree of functional conservation of genetic control pathways from human to mouse. The human placenta and mouse placenta show structural similarities but there has been no systematic attempt to assess their molecular similarities or differences. We built a comprehensive database of protein and microarray data for the highly vascular exchange region micro-dissected from the human and mouse placenta near-term. Abnormalities in this region are associated with two of the most common and serious complications of human pregnancy, maternal preeclampsia (PE) and fetal intrauterine growth restriction (IUGR), each disorder affecting ~5% of all pregnancies. To compare the gene expression patterns in the vascular exchange regions of the human (villus tree) and mouse (labyrinth) placenta. Experiment Overall Design: Mouse labyrinth tissue was micro-dissected form naturally mated crosses of C57Bl/6J mice. Placentas were individually dissected on embryonic day 17.5. From each litter ¼ of the tissue were set aside for RNA extraction and microarray analysis and ¾ for cellular fractionation and proteomic analysis, as recently described (Kislinger et al., 2006). Human villous trees were dissected from term normal placenta delivered by cesarean section from a term pregnancy (~ 38 weeks). Tissue was divided for organellar fractionation and RNA extraction.
Project description:Preeclampsia is a serious pregnancy-induced disorder unique to humans affecting 4.6% of pregnancies worldwide. Advances in the detection, prevention and treatment of preeclampsia have been poor due to our inadequate understanding of its pathogenesis. Here, we perform a multiomics study on early pregnancy placental biopsies (chorionic villus samples) from pregnancies that developed preterm and term preeclampsia compared to normotensive controls. Using an integrative multivariate approach, we uncovered distinct molecular signatures: preterm preeclampsia was strongly associated with dysregulated lipoprotein metabolism, while term preeclampsia exhibited alterations in inflammatory pathways, notch signaling and ribosome assembly. These results challenge the prevailing notion that term preeclampsia is unrelated to early placental pregnancy dysfunction. Our study provides critical insights into the early pregnancy aberrations underlying both preterm and term preeclampsia, paving the way for novel predictive biomarker and targeted preventative treatments. This work represents a significant step towards unravelling the complex etiology of preeclampsia and improving maternal and perinatal health outcomes.
Project description:Genes encoding transcription factors function as hubs in gene regulatory networks because they encode DNA-binding proteins, which bind to promoters that carry their binding sites. In the present work we have studied gene regulatory networks defined by genes with transcripts belonging to different mRNA abundance classes in the small intestinal epithelial cell. The focus is the rewiring that occurs in transcription factor hubs in these networks during the differentiation of the small intestinal epithelial cell while it migrates along the crypt-villus axis and during its development from a fetal endodermal cell to a mature adult villus epithelial cell. We have generated transcriptome data for mouse small intestinal villus, crypt and fetal intestinal epithelial cells. In addition we have generated metabolome data from crypt and villus cells. Our results show that the intestinal crypt transcription factor hubs that are rewired during differentiation are involved in the cell cycle process (E2F, NF-Y) and stem cell maintenance (c-Myc). In contrast the villi are dominated by a HNF-4 villus hub, which is rewired during differentiation by the addition of network genes with relevance for lipoprotein synthesis and lipid absorption. Moreover, we have identified a villus NF-kB hub, which was revealed by comparison of the villus and endoderm transcriptomes. The rewiring of the NF-kB villus hub during intestinal development reflects transcriptional activity established by host and microflora interactions. To aid in the mining of our results we have developed a web portal (http://gastro.imbg.ku.dk/mousecv/) allowing easy linkage between the transcriptomic data, biological processes and functions. Keywords: Cell type comparison
Project description:Genes encoding transcription factors function as hubs in gene regulatory networks because they encode DNA-binding proteins, which bind to promoters that carry their binding sites. In the present work we have studied gene regulatory networks defined by genes with transcripts belonging to different mRNA abundance classes in the small intestinal epithelial cell. The focus is the rewiring that occurs in transcription factor hubs in these networks during the differentiation of the small intestinal epithelial cell while it migrates along the crypt-villus axis and during its development from a fetal endodermal cell to a mature adult villus epithelial cell. We have generated transcriptome data for mouse small intestinal villus, crypt and fetal intestinal epithelial cells. In addition we have generated metabolome data from crypt and villus cells. Our results show that the intestinal crypt transcription factor hubs that are rewired during differentiation are involved in the cell cycle process (E2F, NF-Y) and stem cell maintenance (c-Myc). In contrast the villi are dominated by a HNF-4 villus hub, which is rewired during differentiation by the addition of network genes with relevance for lipoprotein synthesis and lipid absorption. Moreover, we have identified a villus NF-kB hub, which was revealed by comparison of the villus and endoderm transcriptomes. The rewiring of the NF-kB villus hub during intestinal development reflects transcriptional activity established by host and microflora interactions. To aid in the mining of our results we have developed a web portal (http://gastro.imbg.ku.dk/mousecv/) allowing easy linkage between the transcriptomic data, biological processes and functions. Experiment Overall Design: Four different sample categories were analyzed. Experiment Overall Design: 1) Small intestinal crypts isolated form 12-weeks old C57BL/6 mice. These samples are in triplicates. Experiment Overall Design: 2) Small intestinal villi isolated form 12-weeks old C57BL/6 mice. These samples are in triplicates. Experiment Overall Design: 3) Embryonic day 12 mesenchyme. These samples are in quadruplicate. each sample is derived from a pool of mesenchymes (10-40) Experiment Overall Design: 4) Embryonic day 12 endoderm. These samples are in quadruplicate. each sample is derived from a pool of endoderms (10-40)
Project description:H3K79me2 ChIP-seq in mouse proximal intestinal Lgr5(hi) stem cells and villus cells Examination of H3K79me2 modifications between Lgr5(hi) stem cells and differentiated villus cells
Project description:Preeclampsia is a serious pregnancy-induced disorder unique to humans affecting 4.6% of pregnancies worldwide. Advances in the detection, prevention and treatment of preeclampsia have been poor due to our inadequate understanding of its pathogenesis. Here, we perform a multiomics study on early pregnancy placental biopsies (chorionic villus samples) from pregnancies that developed preterm and term preeclampsia compared to normotensive controls. Using an integrative statistical approach we discovered preterm preeclampsia was highly associated with lipoprotein metabolism whereas term preeclampsia was associated with inflammatory pathways and notch signaling. Melanophilin was identified as significantly reduced in early pregnancy placenta from term preeclampsia. Loss of melanophilin was required for syncytialization but excess loss disrupts syncytiotrophoblast function driving the production of antiangiogenic factors known to drive preeclampsia. Our study challenges the dogma that term preeclampsia is not associated with early placental pregnancy dysfunction and provides critical insight into the early pregnancy dysfunction underlying preeclampsia, opening up new avenues for predictive biomarker and preventative treatment discovery.
Project description:Innate immunity is a crucial mechanism for protecting the maternal-fetal interface, whereas little is known about the placenta in chronic HIV-1 infection in mothers treated with antiretroviral therapy (ART). The maternal-fetal interface, we previously observed an enrichment of antiviral factors and inflammatory components in HIV-1 infection. TRIM family proteins are potent antagonists of viral replication; however, others can promote viral replication by ubiquitinating and degrading specific innate immune signalling proteins. We verified the expression of genes involved in innate immunity focusing on the TRIM gene profile in placental tissue (villus and decidua) from HIV-1-infected mothers. We conducted RNA sequencing of placental tissue (villus and decidua) from HIV-1 infected and control mothers. DEGs validation performed by the RT-qPCR method confirms the upregulation of TRIM21 and TRIM39 in both the decidua and the villus of HIV-1-infected samples.