An Oct4‐Sall4‐Nanog network controls developmental progression in the pre‐implantation mouse embryo

Autor: Mylene W.M. Yao, Kin Fai Au, Denise E. Leong, Kira Foygel, Wing Hung Wong, Meng How Tan
Rok vydání: 2013
Předmět:
Male
pre-implantation development
Gene regulatory network
Embryo Culture Techniques
Transcriptome
Mice
pluripotency factors
transcriptional networks
0302 clinical medicine
Gene Regulatory Networks
DNA (Cytosine-5-)-Methyltransferases
Oligonucleotide Array Sequence Analysis
Genetics
Regulation of gene expression
0303 health sciences
Gene knockdown
Applied Mathematics
Gene Expression Regulation
Developmental
Embryo
Nanog Homeobox Protein
DNA-Binding Proteins
Computational Theory and Mathematics
Mice
Inbred DBA
Gene Knockdown Techniques
embryonic structures
Female
General Agricultural and Biological Sciences
Information Systems
Homeobox protein NANOG
animal structures
Embryonic Development
Biology
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Animals
Embryonic Stem Cells
030304 developmental biology
Homeodomain Proteins
General Immunology and Microbiology
Gene Expression Profiling
Embryo
Mammalian
Embryonic stem cell
Mice
Inbred C57BL
MicroRNAs
Blastocyst
Octamer Transcription Factor-3
030217 neurology & neurosurgery
Transcription Factors
Zdroj: Molecular Systems Biology
ISSN: 1744-4292
Popis: Coordination of many biological processes is necessary for mammalian pre-implantation embryo development. The underlying regulatory network was mapped through mathematical modeling, gene-specific knockdowns, and profiling of pooled embryos, single embryos, and single cells.
An integrated Oct4-Sall4-Nanog regulatory network of protein-coding genes and microRNAs governs developmental progression in pre-implantation mouse embryos. While many target genes are common between embryos and embryonic stem cells (ESCs), pluripotency factors regulate the expression of many metabolism- and transport-related genes only in embryos but not in stem cells. The expression of some genes, including the DNA methyltransferase Dnmt3b, correlates strongly with the extent to which an embryo depleted of Oct4, Sall4, or Nanog can develop. In wild-type embryos and ESCs, a coherent feed-forward loop buffers the expression of Dnmt3b against intrinsic fluctuations in the levels of the pluripotency factors.
Landmark events occur in a coordinated manner during pre-implantation development of the mammalian embryo, yet the regulatory network that orchestrates these events remains largely unknown. Here, we present the first systematic investigation of the network in pre-implantation mouse embryos using morpholino-mediated gene knockdowns of key embryonic stem cell (ESC) factors followed by detailed transcriptome analysis of pooled embryos, single embryos, and individual blastomeres. We delineated the regulons of Oct4, Sall4, and Nanog and identified a set of metabolism- and transport-related genes that were controlled by these transcription factors in embryos but not in ESCs. Strikingly, the knockdown embryos arrested at a range of developmental stages. We provided evidence that the DNA methyltransferase Dnmt3b has a role in determining the extent to which a knockdown embryo can develop. We further showed that the feed-forward loop comprising Dnmt3b, the pluripotency factors, and the miR-290-295 cluster exemplifies a network motif that buffers embryos against gene expression noise. Our findings indicate that Oct4, Sall4, and Nanog form a robust and integrated network to govern mammalian pre-implantation development.
Databáze: OpenAIRE
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