Project description:We used an in vitro cardiomyocyte differentiation system with inducible Hey1 or Hey2 expression to study target gene regulation in cardiomyocytes (CM) generated from murine embryonic stem cells (ESC). The effects of Hey1 and Hey2 are largely redundant, but cell type specific. The number of regulated genes is comparable between ESC and CM, but the total number of binding sites is much higher, especially in ESC, targeting mainly genes involved in transcriptional regulation and developmental processes. Repression by Hey generally correlates with the extent of Hey-binding to target promoters, subsequent Hdac recruitment and lower histone acetylation. Functionally, treatment with the Hdac inhibitor TSA abolished Hey target gene regulation. However, in CM the repressive effect of Hey-binding is lost for a subset of genes. These lack Hey-dependent histone deacetylation in CM and are enriched for binding sites of cardiac specific activators like Srf, Nkx2-5, and Gata4. ES cells and cardiomyocytes with Hey1 or Hey2 overexpression were compared to control cells
Project description:We used an in vitro cardiomyocyte differentiation system with inducible Hey1 or Hey2 expression to study target gene regulation in cardiomyocytes (CM) generated from murine embryonic stem cells (ESC). The effects of Hey1 and Hey2 are largely redundant, but cell type specific. The number of regulated genes is comparable between ESC and CM, but the total number of binding sites is much higher, especially in ESC, targeting mainly genes involved in transcriptional regulation and developmental processes. Repression by Hey generally correlates with the extent of Hey-binding to target promoters, subsequent Hdac recruitment and lower histone acetylation. Functionally, treatment with the Hdac inhibitor TSA abolished Hey target gene regulation. However, in CM the repressive effect of Hey-binding is lost for a subset of genes. These lack Hey-dependent histone deacetylation in CM and are enriched for binding sites of cardiac specific activators like Srf, Nkx2-5, and Gata4. Control cells and cells with Hey1 or Hey2 overexpression, no replicates
Project description:Over the past few years, studies of DNA isolated from human fossils and archaeological remains have generated considerable novel insight into the history of our species. Several landmark papers have described the genomes of ancient human ancestors and have demonstrated that contemporary humans harbour genetic material from ancient close relatives, the Neanderthals and Denisovans, and that ancient human individuals are often genetically distinct from nearby extant populations whilst also showing affinities with populations from further afield. Across West Eurasia, there is growing genetic evidence of large-scale, dynamic population movements over the period between 10,000 to 2,000 years ago, such that the ancestry across present-day populations is likely to be a mixture of several ancient groups. Whilst these efforts are bringing the details of West Eurasian prehistory into increasing focus, studies aimed at understanding the processes behind the generation of the current West Eurasian genetic landscape have been limited by the number of populations sampled, or have been either too regional or global in their outlook. Here, using recently described haplotype-based techniques, we present the results of a systematic survey of recent admixture history across Western Eurasia and show that admixture is a universal property across almost all groups. Admixture in all regions except North Western Europe involved the influx of genetic material from outside of West Eurasia, which we date to specific time periods. Within Northern, Western, and Central Europe, admixture tended to occur between local groups during the period 300 to 1200CE. Comparisons of the genetic profiles of West Eurasians before and after admixture show that population movements within the last 1500 years are likely to have maintained differentiation amongst groups. Our analysis provides a timeline of the gene flow events that have generated the contemporary genetic landscape of West Eurasia. 20 individuals from Croatia included as part of an analysis of admixture in West Eurasia
Project description:In this study we identify genes, that are bound by Kdm4a and Kdm4c in L-GMP cells. MLL-AF9 transformed L-GMP cell lines conditional knockout for Kdm4a, b and c, were derived from leukemic mice. The cells were treated with 4-hydroxytamoxifen and chromatin was prepared from untreated cells (Ctrl) and cells treated for 96hr.
Project description:We used an in vitro cardiomyocyte differentiation system with inducible Hey1 or Hey2 expression to study target gene regulation in cardiomyocytes (CM) generated from murine embryonic stem cells (ESC). The effects of Hey1 and Hey2 are largely redundant, but cell type specific. The number of regulated genes is comparable between ESC and CM, but the total number of binding sites is much higher, especially in ESC, targeting mainly genes involved in transcriptional regulation and developmental processes. Repression by Hey generally correlates with the extent of Hey-binding to target promoters, subsequent Hdac recruitment and lower histone acetylation. Functionally, treatment with the Hdac inhibitor TSA abolished Hey target gene regulation. However, in CM the repressive effect of Hey-binding is lost for a subset of genes. These lack Hey-dependent histone deacetylation in CM and are enriched for binding sites of cardiac specific activators like Srf, Nkx2-5, and Gata4.
Project description:We used an in vitro cardiomyocyte differentiation system with inducible Hey1 or Hey2 expression to study target gene regulation in cardiomyocytes (CM) generated from murine embryonic stem cells (ESC). The effects of Hey1 and Hey2 are largely redundant, but cell type specific. The number of regulated genes is comparable between ESC and CM, but the total number of binding sites is much higher, especially in ESC, targeting mainly genes involved in transcriptional regulation and developmental processes. Repression by Hey generally correlates with the extent of Hey-binding to target promoters, subsequent Hdac recruitment and lower histone acetylation. Functionally, treatment with the Hdac inhibitor TSA abolished Hey target gene regulation. However, in CM the repressive effect of Hey-binding is lost for a subset of genes. These lack Hey-dependent histone deacetylation in CM and are enriched for binding sites of cardiac specific activators like Srf, Nkx2-5, and Gata4.
Project description:We demonstrate that transcriptomic profiling of the NER mutant ercc-1 offers better understanding of the complex phenotypes of ercc-1 deficiency in C. elegans, as it does in mammalian models. There is a transcriptomic shift in ercc-1 mutants that suggests a stochastic impairment of growth and development, with a shift towards a higher proportion of males in the population. Extensive phenotypic analyses confirm that NER deficiency in C. elegans leads to severe developmental and growth defects and a reduced replicative lifespan, although post-mitotic lifespan is not affected. Results suggest that these defects are caused by an inability to cope with randomly occurring DNA damage, which may interfere with transcription and replication. The study investigates the developmental and aging phenotypes of different NER deficient C. elegans mutants (xpa-1, ercc-1, xpf-1 and xpg-1), where the transcriptomic profile of ercc-1 mutant is presented. We show that loss of NER function does not affect post-mitotic lifespan, but leads to impaired embryogenesis, germ cell and larval development and causes a reduced replicative lifespan. Phenotypes are most pronounced in ercc-1, xpf-1 and xpg-1 mutant animals. We provide evidence that this more pronounced phenotype is likely caused by the fact that these genes are involved in multiple repair pathways besides NER. Furthermore, transcriptional profiling of ercc-1 mutants confirms these observations, showing that growth and developmental pathways are underrepresented but that insulin signaling is not affected. Our analysis suggests that XPA-1, ERCC-1, XPF-1 and XPG-1 protect animals against replicative aging by preventing the accumulation of randomly acquired DNA damage. Eight mixed stage C. elegans samples were run on Affymetrix GeneChip C. elegans Genome Arrays. Four samples belong to ercc-1 mutant group and four to the wild-type, N2.