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Understanding the molecular circuitry of cell lineage specification in the early mouse embryo.

Bergsmedh A, Donohoe ME, Hughes RA, Hadjantonakis AK - Genes (Basel) (2011)

Bottom Line: Pluripotent stem cells hold great promise for cell-based therapies in regenerative medicine.However, critical to understanding and exploiting mechanisms of cell lineage specification, epigenetic reprogramming, and the optimal environment for maintaining and differentiating pluripotent stem cells is a fundamental knowledge of how these events occur in normal embryogenesis.The early mouse embryo has provided an excellent model to interrogate events crucial in cell lineage commitment and plasticity, as well as for embryo-derived lineage-specific stem cells and induced pluripotent stem (iPS) cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10065, USA. anna.bergsmedh@me.com.

ABSTRACT
Pluripotent stem cells hold great promise for cell-based therapies in regenerative medicine. However, critical to understanding and exploiting mechanisms of cell lineage specification, epigenetic reprogramming, and the optimal environment for maintaining and differentiating pluripotent stem cells is a fundamental knowledge of how these events occur in normal embryogenesis. The early mouse embryo has provided an excellent model to interrogate events crucial in cell lineage commitment and plasticity, as well as for embryo-derived lineage-specific stem cells and induced pluripotent stem (iPS) cells. Here we provide an overview of cell lineage specification in the early (preimplantation) mouse embryo focusing on the transcriptional circuitry and epigenetic marks necessary for successive differentiation events leading to the formation of the blastocyst.

No MeSH data available.


Post translation modifications (PTMs) occur on the histone tails and a PTM code designates genes “on” or “off”. In early embryos and ES cells, modifications can dictate gene activation or repression. One example is the bivalent marks found in undifferentiated ES cells in which histone H3 lysine 27 is trimethylated (H3K27me3) and histone H3 lysine 4 is trimethylated (H3K4me3). H3K27me3 is typically a repressive mark whereas H3K4me3 denotes an active gene.
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f6-genes-02-00420: Post translation modifications (PTMs) occur on the histone tails and a PTM code designates genes “on” or “off”. In early embryos and ES cells, modifications can dictate gene activation or repression. One example is the bivalent marks found in undifferentiated ES cells in which histone H3 lysine 27 is trimethylated (H3K27me3) and histone H3 lysine 4 is trimethylated (H3K4me3). H3K27me3 is typically a repressive mark whereas H3K4me3 denotes an active gene.

Mentions: Not only does the mechanical chromatin packaging determine heterochromatic vs. euchromatic state but covalent post-translational modifications (PTMs) on the nucleosomal histone tails may identify active genomic regions (Figure 6). Histone PTMs may provide a fundamental way of regulating DNA accessibility during gene transcription, DNA replication, and DNA replication, and DNA damage repair [31] Methylation of histones may occur at multiple lysine and arginine residues. Up to three methyl groups at each lysine may be produced. For example, histone H3 lysine 4 trimethylation (H3K4me3) typically denotes a transcriptionally active genomic region, whereas histone H3 lysine 27 trimethylation (H3K27me3) signifies an inactive or repressed region. These repressed regions in early development are genes involved in pluripotency and lineage differentiation [32–34]. These PTMs provide a “landing pad” or scaffold for transcriptional co-activators or co-repressors. But, this combinatorial pattern of histone marking is rather complex. Although ES cells show a globally open chromatin structure and are enriched for active H3K4 methylation marks, only a subset of promoters with H3K4 methylation show enrichment for elongating RNAP II and histone H3 lysine 36 di- or tri-methylation (H3K36 me2 or me3) signifying active transcription through the loci. Histone PTMs are some of the earliest marks of linage segregation with both the ICM and TE displaying differential histone modifications [35]. In the ICM, the Oct4 promoter has increased histone 4 lysine 8 acetylation (H4K8ac) and H3K4me3 [36]. This contrasts to the Oct4 promoter in the TE, which has increased H3K9me2 (a repressive mark). Torres-Padilla, et al describe other marks, histone 3 arginine 17 and arginine 26 monomethylation (H3R17me and H3R26me), that differ in the mouse blastomeres as early as the 4-cell stage [37]. They show that there are higher levels of H3R17me and H3R26me in cells destined to become the ICM, whereas, lower H3R17me and H3R26me in the TE fated cells. Ectopic expression of Carm1 (the H3-specific arginine methyltransferase responsible for placing the H3R17 and H3R26 methylation marks) into one of the blastomeres at the 2-cell embryo stage shows that both the Nanog and Sox2 pluripotent genes get up regulated and fated to ICM [37]. Thus, PTMs such as histone arginine methylation may mark the cellular fate decisions towards pluripotency in the early mouse embryo. Additional PTMs as well as the writers and readers of these marks may also signify differential cell fates.


Understanding the molecular circuitry of cell lineage specification in the early mouse embryo.

Bergsmedh A, Donohoe ME, Hughes RA, Hadjantonakis AK - Genes (Basel) (2011)

Post translation modifications (PTMs) occur on the histone tails and a PTM code designates genes “on” or “off”. In early embryos and ES cells, modifications can dictate gene activation or repression. One example is the bivalent marks found in undifferentiated ES cells in which histone H3 lysine 27 is trimethylated (H3K27me3) and histone H3 lysine 4 is trimethylated (H3K4me3). H3K27me3 is typically a repressive mark whereas H3K4me3 denotes an active gene.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927619&req=5

f6-genes-02-00420: Post translation modifications (PTMs) occur on the histone tails and a PTM code designates genes “on” or “off”. In early embryos and ES cells, modifications can dictate gene activation or repression. One example is the bivalent marks found in undifferentiated ES cells in which histone H3 lysine 27 is trimethylated (H3K27me3) and histone H3 lysine 4 is trimethylated (H3K4me3). H3K27me3 is typically a repressive mark whereas H3K4me3 denotes an active gene.
Mentions: Not only does the mechanical chromatin packaging determine heterochromatic vs. euchromatic state but covalent post-translational modifications (PTMs) on the nucleosomal histone tails may identify active genomic regions (Figure 6). Histone PTMs may provide a fundamental way of regulating DNA accessibility during gene transcription, DNA replication, and DNA replication, and DNA damage repair [31] Methylation of histones may occur at multiple lysine and arginine residues. Up to three methyl groups at each lysine may be produced. For example, histone H3 lysine 4 trimethylation (H3K4me3) typically denotes a transcriptionally active genomic region, whereas histone H3 lysine 27 trimethylation (H3K27me3) signifies an inactive or repressed region. These repressed regions in early development are genes involved in pluripotency and lineage differentiation [32–34]. These PTMs provide a “landing pad” or scaffold for transcriptional co-activators or co-repressors. But, this combinatorial pattern of histone marking is rather complex. Although ES cells show a globally open chromatin structure and are enriched for active H3K4 methylation marks, only a subset of promoters with H3K4 methylation show enrichment for elongating RNAP II and histone H3 lysine 36 di- or tri-methylation (H3K36 me2 or me3) signifying active transcription through the loci. Histone PTMs are some of the earliest marks of linage segregation with both the ICM and TE displaying differential histone modifications [35]. In the ICM, the Oct4 promoter has increased histone 4 lysine 8 acetylation (H4K8ac) and H3K4me3 [36]. This contrasts to the Oct4 promoter in the TE, which has increased H3K9me2 (a repressive mark). Torres-Padilla, et al describe other marks, histone 3 arginine 17 and arginine 26 monomethylation (H3R17me and H3R26me), that differ in the mouse blastomeres as early as the 4-cell stage [37]. They show that there are higher levels of H3R17me and H3R26me in cells destined to become the ICM, whereas, lower H3R17me and H3R26me in the TE fated cells. Ectopic expression of Carm1 (the H3-specific arginine methyltransferase responsible for placing the H3R17 and H3R26 methylation marks) into one of the blastomeres at the 2-cell embryo stage shows that both the Nanog and Sox2 pluripotent genes get up regulated and fated to ICM [37]. Thus, PTMs such as histone arginine methylation may mark the cellular fate decisions towards pluripotency in the early mouse embryo. Additional PTMs as well as the writers and readers of these marks may also signify differential cell fates.

Bottom Line: Pluripotent stem cells hold great promise for cell-based therapies in regenerative medicine.However, critical to understanding and exploiting mechanisms of cell lineage specification, epigenetic reprogramming, and the optimal environment for maintaining and differentiating pluripotent stem cells is a fundamental knowledge of how these events occur in normal embryogenesis.The early mouse embryo has provided an excellent model to interrogate events crucial in cell lineage commitment and plasticity, as well as for embryo-derived lineage-specific stem cells and induced pluripotent stem (iPS) cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10065, USA. anna.bergsmedh@me.com.

ABSTRACT
Pluripotent stem cells hold great promise for cell-based therapies in regenerative medicine. However, critical to understanding and exploiting mechanisms of cell lineage specification, epigenetic reprogramming, and the optimal environment for maintaining and differentiating pluripotent stem cells is a fundamental knowledge of how these events occur in normal embryogenesis. The early mouse embryo has provided an excellent model to interrogate events crucial in cell lineage commitment and plasticity, as well as for embryo-derived lineage-specific stem cells and induced pluripotent stem (iPS) cells. Here we provide an overview of cell lineage specification in the early (preimplantation) mouse embryo focusing on the transcriptional circuitry and epigenetic marks necessary for successive differentiation events leading to the formation of the blastocyst.

No MeSH data available.