Project description:We used epigenetic profiling to map active enhancers in the developing human limb and cortex as described in two published studies: Cotney J, Leng J, Yin J, Reilly SK et al. The evolution of lineage-specific regulatory activities in the human embryonic limb. Cell 2013;154(1):185-96. Reilly SK, Yin J, Ayoub AE, Emera D et al. Evolutionary changes in promoter and enhancer activity during human corticogenesis. Science 2015;347(6226):1155-9. We also used ChIP-seq to map binding sites for the chromatin modifier CHD8 in the developing human brain, as described in one published study: Cotney J, Muhle RA, Sanders SJ, Liu L et al. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun 2015;6:6404. We are also depositing primary human sequence reads related to processed datasets in the Gene Expression Omnibus under the following accession numbers: GSE42413(Cotney et al. 2013); GSE63649(Reilly... (for more see dbGaP study page.)
Project description:Chavez2009 - a core regulatory network of OCT4 in human embryonic stem cells
A core OCT4-regulated network has been identified as a test case, to analyase stem cell characteristics and cellular differentiation.
This model is described in the article:
In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach.
Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R
BMC Genomics, 2009, 10:314
BACKGROUND: The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal are controlled by a transcription regulatory network governed by the transcription factors OCT4, SOX2 and NANOG. Recent studies on reprogramming somatic cells to induced pluripotent stem cells highlight OCT4 as a key regulator of pluripotency.
RESULTS: We have carried out an integrated analysis of high-throughput data (ChIP-on-chip and RNAi experiments along with promoter sequence analysis of putative target genes) and identified a core OCT4 regulatory network in human embryonic stem cells consisting of 33 target genes. Enrichment analysis with these target genes revealed that this integrative analysis increases the functional information content by factors of 1.3 - 4.7 compared to the individual studies. In order to identify potential regulatory co-factors of OCT4, we performed a de novo motif analysis. In addition to known validated OCT4 motifs we obtained binding sites similar to motifs recognized by further regulators of pluripotency and development; e.g. the heterodimer of the transcription factors C-MYC and MAX, a prerequisite for C-MYC transcriptional activity that leads to cell growth and proliferation.
CONCLUSION: Our analysis shows how heterogeneous functional information can be integrated in order to reconstruct gene regulatory networks. As a test case we identified a core OCT4-regulated network that is important for the analysis of stem cell characteristics and cellular differentiation. Functional information is largely enriched using different experimental results. The de novo motif discovery identified well-known regulators closely connected to the OCT4 network as well as potential new regulators of pluripotency and differentiation. These results provide the basis for further targeted functional studies.
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Project description:This SuperSeries is composed of the following subset Series: GSE34904: NANOG-OCT4-SOX2 Regulatory Module in Human Embryonic Stem Cells (dataset 1) GSE34912: NANOG-OCT4-SOX2 Regulatory Module in Human Embryonic Stem Cells (dataset 2) GSE34918: NANOG-OCT4-SOX2 Regulatory Module in Human Embryonic Stem Cells (dataset 3) GSE34920: NANOG-OCT4-SOX2 Regulatory Module in Human Embryonic Stem Cells (dataset 4) Refer to individual Series
Project description:Gene set and sub-network enrichment analysis provides an integrated approach for identifying gene regulatory networks underlying development. Anuran development is a coordinated process, and levels of mRNA are first dominated by maternally deposited genes, followed by active transcription of embryonic genes as the embryo undergoes morphogenesis and organ formation. The objectives of this study were to characterize early gene regulatory networks underlying Silurana tropicalis development. A custom Agilent 4 x 44 K microarray was developed to characterize networks during early development (1, 17, 36, 96 hpf). Cluster analysis revealed that each stage showed unique gene expression profiles and that 1 hpf was most different than the other three stages. There were > 8000 unique gene probes (p<0.01, FDR = 5%) that were differentially expressed between 1 hpf (2 cell stage) and 17 hpf and > 2000 gene probes differentially expressed between 36 hpf and 96 hpf. Genes higher in abundance (>100-fold) at 1 hpf compared to 17 hpf included oocyte-specific histone RNA stem-loop-binding protein 2, mitogen-activated protein kinase 14, and cyclin B5, suggesting these transcripts are maternally inherited or actively transcribed at fertilization. Gene ontology revealed that genes involved in nucleosome assembly, cell division, pattern specification, neurotransmission, and general metabolism were increasingly regulated throughout development, consistent with active development. In the period between 17-36 hpf, gene networks that play a role in organogenesis and organ function, including those related to the heart (heart morphogenesis, central nervous system (olfactory bulb development, dopamine metabolism), and kidney (renal reabsorption, water balance) were activated while between 36-96 hpf, networks involving in gut development, immune responses, lipid metabolism, hormone signaling, and brain development were prevalent. This study increases understanding of the spatiotemporal S. tropicalis embryonic development using gene regulatory networks. Gene expression analysis was performed with four biological replicates for four developmental stages (n = 16). Stages were NF stages 2, 16, 34, and 46.
Project description:How the limb bud gives rise to the limb is a classic paradigm of model organism developmental biology, which is uncharted in human, and incompletely understood at the molecular and cellular levels. Here, we analyze the transcriptomes of 27,426 cells from 5 human embryonic limbs between 5 and 8 weeks post-conception to build a high-resolution single-cell transcriptome atlas of embryonic limb development. We developed a new toolkit, “PLOGS”, to visualize genes guiding cell fate decisions. Using this approach, we decipher the developmental trajectories of the major mesodermal lineages, and identify regulatory factors in limb development. For the skeletal muscle lineage, we show how Pax3+ cells directly differentiate towards embryonic myocytes, as well as give rise to the Pax7+ stem cell reservoir. For the osteoblast lineage, we reveal development out of the perichondrium for the first time. Moreover, we constructed a global cell–cell signaling map, and identified an interaction between endothelial cells and muscle stem cells which directs myocyte differentiation. We highlight the importance of the cell signaling circuitry to mechanisms underlying human developmental diseases. Overall, this study illustrates the first whole human body structure charted comprehensively by single cell transcriptomics, and provides a valuable resource for the community accessible via an online portal.
Project description:The evolution of human anatomical features likely involved changes in gene regulation during development. However, the nature and extent of human specific developmental regulatory functions remain unknown. We obtained a genome-wide view of cis regulatory evolution in human embryonic tissues by comparing the histone modification H3K27ac, which provides a quantitative readout of promoter and enhancer activity, during human, rhesus, and mouse limb development. Based on increased H3K27ac, we find that 13% of promoters and 11% of enhancers have gained activity on the human lineage since the human-rhesus divergence. These gains largely arose by modification of ancestral regulatory activities in the limb or potential co-option from other tissues and are likely to have heterogeneous genetic causes. Most enhancers that exhibit gain of activity in humans originated in mammals. Gains at promoters and enhancers in the human limb are associated with increased gene expression, suggesting they include molecular drivers of human morphological evolution. ChIP-Seq and RNA-Seq of autopod tissue of developing limb buds of Human (E33-E47), rhesus (E31-E36), and mouse (E10.5-E13.5). No raw data are provided for human samples. Human alignments were anonymized by removing sequence information and converting to bed format.
Project description:The regulatory landscape of the human genome during organogenesis is undescribed for most tissues. We used ChIP-seq to survey histone modifications in 13 human embryonic tissues. We describe patterns of both common and tissue-specific marking of promoter activation and repression and use enhancer usage to infer regulatory pathways.