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Prenatal alcohol exposure and cellular differentiation: a role for Polycomb and Trithorax group proteins in FAS phenotypes?

Veazey KJ, Muller D, Golding MC - Alcohol Res (2013)

Bottom Line: Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell's identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin.Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects.Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA.

ABSTRACT
Exposure to alcohol significantly alters the developmental trajectory of progenitor cells and fundamentally compromises tissue formation (i.e., histogenesis). Emerging research suggests that ethanol can impair mammalian development by interfering with the execution of molecular programs governing differentiation. For example, ethanol exposure disrupts cellular migration, changes cell-cell interactions, and alters growth factor signaling pathways. Additionally, ethanol can alter epigenetic mechanisms controlling gene expression. Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell's identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin. Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects. Two crucial enzyme complexes--the Polycomb and Trithorax proteins--are central to the epigenetic programs controlling the intricate balance between self-renewal and the execution of cellular differentiation, with diametrically opposed functions. Prenatal ethanol exposure may disrupt the functions of these two enzyme complexes, altering a crucial aspect of mammalian differentiation. Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder.

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Related in: MedlinePlus

Transcriptional regulation by the Polycomb and Trithorax complexes. Polycomb repressive complex 1 (PRC1) consists of four core proteins including: polyhomeotic homolog (PHC), ring finger protein 1A or 1B (RING1A or RING1B), B-lymphoma Mo-MLV insertion region 1 homolog (BMI1), and chromobox homolog (CBX). The RING1A/RING1B subunits are the catalytic engine of the PRC1 complex and carry out ubiquitination of histone 2A at lysine 119 (H2AK119ub). PRC2 consists of four core proteins including: embryonic ectoderm development (EED), enhancer of zeste 2 (EZH2), suppressor of zeste 12 (SUZ12), and polycomb like (PCL). EZH2 serves as the catalytic subunit of PRC2 and trimethylates lysine 27 on histone 3 (H3K27me3). Current models suggest that H3K27me3 generated by PRC2 facilitates compaction of chromatin leading to the repression of gene expression. Subsequently, the CBX subunit of the PRC1 complex recognizes H3K27me3, and the RING1A/RING1B subunits of PRC1 ubiquitinate H2AK119 to facilitate the maintenance of the repressed state.
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f2a-arcr-35-1-77: Transcriptional regulation by the Polycomb and Trithorax complexes. Polycomb repressive complex 1 (PRC1) consists of four core proteins including: polyhomeotic homolog (PHC), ring finger protein 1A or 1B (RING1A or RING1B), B-lymphoma Mo-MLV insertion region 1 homolog (BMI1), and chromobox homolog (CBX). The RING1A/RING1B subunits are the catalytic engine of the PRC1 complex and carry out ubiquitination of histone 2A at lysine 119 (H2AK119ub). PRC2 consists of four core proteins including: embryonic ectoderm development (EED), enhancer of zeste 2 (EZH2), suppressor of zeste 12 (SUZ12), and polycomb like (PCL). EZH2 serves as the catalytic subunit of PRC2 and trimethylates lysine 27 on histone 3 (H3K27me3). Current models suggest that H3K27me3 generated by PRC2 facilitates compaction of chromatin leading to the repression of gene expression. Subsequently, the CBX subunit of the PRC1 complex recognizes H3K27me3, and the RING1A/RING1B subunits of PRC1 ubiquitinate H2AK119 to facilitate the maintenance of the repressed state.

Mentions: The PcG proteins and the genes encoding them originally were discovered over 30 years ago as key regulators of the processes that specify which end of the embryo forms the head and which the rear during the development of Drosophila (Lewis 1978). Since then, researchers have found that these gene families encode essential regulators governing mammalian processes of cellular determination and lineage-specific patterns of differentiation. In mammals, two major PcG complexes have been characterized that modify chromatin structure; these are called Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). Each complex is composed of several proteins with different biochemical functions, many of which are not well understood (see figure 2). PRC1 acts by mediating the ubiquitination of the 119th lysine residue of histone H2A; this is achieved by two of the PRC1 proteins called ring finger protein 1A and 1B (RING1A and RING1B) (Wang et al. 2004). This posttranslational modification pushes the local chromatin structure towards a transcriptionally repressive state and its proper establishment is essential to the coordinated silencing of genes through-out mammalian development (Boyer et al. 2006; Wang et al. 2004). In embryonic stem cells, histone ubiquitination stabilizes the presence of an enzyme called RNA polymerase II (which is required for gene expression) at bivalent chromatin domains and is crucial for maintaining the pluripotent state of undifferentiated cells (Ku et al. 2008).


Prenatal alcohol exposure and cellular differentiation: a role for Polycomb and Trithorax group proteins in FAS phenotypes?

Veazey KJ, Muller D, Golding MC - Alcohol Res (2013)

Transcriptional regulation by the Polycomb and Trithorax complexes. Polycomb repressive complex 1 (PRC1) consists of four core proteins including: polyhomeotic homolog (PHC), ring finger protein 1A or 1B (RING1A or RING1B), B-lymphoma Mo-MLV insertion region 1 homolog (BMI1), and chromobox homolog (CBX). The RING1A/RING1B subunits are the catalytic engine of the PRC1 complex and carry out ubiquitination of histone 2A at lysine 119 (H2AK119ub). PRC2 consists of four core proteins including: embryonic ectoderm development (EED), enhancer of zeste 2 (EZH2), suppressor of zeste 12 (SUZ12), and polycomb like (PCL). EZH2 serves as the catalytic subunit of PRC2 and trimethylates lysine 27 on histone 3 (H3K27me3). Current models suggest that H3K27me3 generated by PRC2 facilitates compaction of chromatin leading to the repression of gene expression. Subsequently, the CBX subunit of the PRC1 complex recognizes H3K27me3, and the RING1A/RING1B subunits of PRC1 ubiquitinate H2AK119 to facilitate the maintenance of the repressed state.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3860417&req=5

f2a-arcr-35-1-77: Transcriptional regulation by the Polycomb and Trithorax complexes. Polycomb repressive complex 1 (PRC1) consists of four core proteins including: polyhomeotic homolog (PHC), ring finger protein 1A or 1B (RING1A or RING1B), B-lymphoma Mo-MLV insertion region 1 homolog (BMI1), and chromobox homolog (CBX). The RING1A/RING1B subunits are the catalytic engine of the PRC1 complex and carry out ubiquitination of histone 2A at lysine 119 (H2AK119ub). PRC2 consists of four core proteins including: embryonic ectoderm development (EED), enhancer of zeste 2 (EZH2), suppressor of zeste 12 (SUZ12), and polycomb like (PCL). EZH2 serves as the catalytic subunit of PRC2 and trimethylates lysine 27 on histone 3 (H3K27me3). Current models suggest that H3K27me3 generated by PRC2 facilitates compaction of chromatin leading to the repression of gene expression. Subsequently, the CBX subunit of the PRC1 complex recognizes H3K27me3, and the RING1A/RING1B subunits of PRC1 ubiquitinate H2AK119 to facilitate the maintenance of the repressed state.
Mentions: The PcG proteins and the genes encoding them originally were discovered over 30 years ago as key regulators of the processes that specify which end of the embryo forms the head and which the rear during the development of Drosophila (Lewis 1978). Since then, researchers have found that these gene families encode essential regulators governing mammalian processes of cellular determination and lineage-specific patterns of differentiation. In mammals, two major PcG complexes have been characterized that modify chromatin structure; these are called Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). Each complex is composed of several proteins with different biochemical functions, many of which are not well understood (see figure 2). PRC1 acts by mediating the ubiquitination of the 119th lysine residue of histone H2A; this is achieved by two of the PRC1 proteins called ring finger protein 1A and 1B (RING1A and RING1B) (Wang et al. 2004). This posttranslational modification pushes the local chromatin structure towards a transcriptionally repressive state and its proper establishment is essential to the coordinated silencing of genes through-out mammalian development (Boyer et al. 2006; Wang et al. 2004). In embryonic stem cells, histone ubiquitination stabilizes the presence of an enzyme called RNA polymerase II (which is required for gene expression) at bivalent chromatin domains and is crucial for maintaining the pluripotent state of undifferentiated cells (Ku et al. 2008).

Bottom Line: Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell's identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin.Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects.Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA.

ABSTRACT
Exposure to alcohol significantly alters the developmental trajectory of progenitor cells and fundamentally compromises tissue formation (i.e., histogenesis). Emerging research suggests that ethanol can impair mammalian development by interfering with the execution of molecular programs governing differentiation. For example, ethanol exposure disrupts cellular migration, changes cell-cell interactions, and alters growth factor signaling pathways. Additionally, ethanol can alter epigenetic mechanisms controlling gene expression. Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell's identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin. Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects. Two crucial enzyme complexes--the Polycomb and Trithorax proteins--are central to the epigenetic programs controlling the intricate balance between self-renewal and the execution of cellular differentiation, with diametrically opposed functions. Prenatal ethanol exposure may disrupt the functions of these two enzyme complexes, altering a crucial aspect of mammalian differentiation. Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder.

Show MeSH
Related in: MedlinePlus