Limits...
Epigenetic factors influencing resistance to nuclear reprogramming.

Pasque V, Jullien J, Miyamoto K, Halley-Stott RP, Gurdon JB - Trends Genet. (2011)

Bottom Line: Transcription factors, chromatin modifications, and noncoding RNAs can increase the efficiency of reprogramming.However, the success of nuclear reprogramming is limited by epigenetic mechanisms that stabilise the state of gene expression in somatic cells and thereby resist efficient reprogramming.We see this as a step towards understanding the mechanisms by which nuclear reprogramming takes place.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.

Show MeSH
Hypothetical model of chromatin state changes at gene regulatory regions during reprogramming and differentiation. Epigenetic reprogramming of chromatin states requires several events, some of which are summarised here. A fully repressed gene (a) must be remodelled to evict repressive nucleosomes, which may contain histone variants such as macroH2A and multiple repressive histone modifications. Once accessible, regulatory regions may be bound by transcriptional regulators with the ability to recruit activities, such as H3K4 methyltransferases. Loss of repressive histone modifications, such as H3K9me2/3, H3K27me2/3 and DNA methylation and demethylation may occur actively or passively through cell divisions. Histone acetylation also strongly increases transcriptional activity (b). The opposite route may lead to transcriptional silencing of differentiation genes during reprogramming towards pluripotency, or silencing of pluripotency genes during cell differentiation. The steps represented may occur simultaneously and/or in a different order according to the gene and system considered. The order of the epigenetic events that occur during nuclear reprogramming may not be in the exact reverse order of the events that occur during cell differentiation.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3814186&req=5

fig0015: Hypothetical model of chromatin state changes at gene regulatory regions during reprogramming and differentiation. Epigenetic reprogramming of chromatin states requires several events, some of which are summarised here. A fully repressed gene (a) must be remodelled to evict repressive nucleosomes, which may contain histone variants such as macroH2A and multiple repressive histone modifications. Once accessible, regulatory regions may be bound by transcriptional regulators with the ability to recruit activities, such as H3K4 methyltransferases. Loss of repressive histone modifications, such as H3K9me2/3, H3K27me2/3 and DNA methylation and demethylation may occur actively or passively through cell divisions. Histone acetylation also strongly increases transcriptional activity (b). The opposite route may lead to transcriptional silencing of differentiation genes during reprogramming towards pluripotency, or silencing of pluripotency genes during cell differentiation. The steps represented may occur simultaneously and/or in a different order according to the gene and system considered. The order of the epigenetic events that occur during nuclear reprogramming may not be in the exact reverse order of the events that occur during cell differentiation.

Mentions: As cells differentiate, their chromatin becomes increasingly condensed. Nuclear volume is indicative of the average extent of chromatin condensation. We estimate the volume of a nucleus (inversely related to condensation) in lymphocytes, non-mammalian red blood cells, and sperm, to be three, eight or 100 times respectively, smaller than that of an ES cell. In all nuclear transfer experiments, both in eggs and oocytes, a nuclear volume increase of 10–30-fold accompanies new gene transcripts [29], chromosomal proteins leave the nucleus and chromosomal protein mobility is increased [30]. Likewise, in heterokaryon experiments, similar changes follow cell fusion [6,7,31]. However, changes in nuclear volumes are not sufficient for gene reactivation because Polycomb-deficient ES cells do not induce pluripotency gene reactivation when fused to human B-lymphocytes but nuclear volume changes remain unperturbed [32]. In Figure 3, we present a hypothetical model of chromosomal changes associated with nuclear reprogramming.


Epigenetic factors influencing resistance to nuclear reprogramming.

Pasque V, Jullien J, Miyamoto K, Halley-Stott RP, Gurdon JB - Trends Genet. (2011)

Hypothetical model of chromatin state changes at gene regulatory regions during reprogramming and differentiation. Epigenetic reprogramming of chromatin states requires several events, some of which are summarised here. A fully repressed gene (a) must be remodelled to evict repressive nucleosomes, which may contain histone variants such as macroH2A and multiple repressive histone modifications. Once accessible, regulatory regions may be bound by transcriptional regulators with the ability to recruit activities, such as H3K4 methyltransferases. Loss of repressive histone modifications, such as H3K9me2/3, H3K27me2/3 and DNA methylation and demethylation may occur actively or passively through cell divisions. Histone acetylation also strongly increases transcriptional activity (b). The opposite route may lead to transcriptional silencing of differentiation genes during reprogramming towards pluripotency, or silencing of pluripotency genes during cell differentiation. The steps represented may occur simultaneously and/or in a different order according to the gene and system considered. The order of the epigenetic events that occur during nuclear reprogramming may not be in the exact reverse order of the events that occur during cell differentiation.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814186&req=5

fig0015: Hypothetical model of chromatin state changes at gene regulatory regions during reprogramming and differentiation. Epigenetic reprogramming of chromatin states requires several events, some of which are summarised here. A fully repressed gene (a) must be remodelled to evict repressive nucleosomes, which may contain histone variants such as macroH2A and multiple repressive histone modifications. Once accessible, regulatory regions may be bound by transcriptional regulators with the ability to recruit activities, such as H3K4 methyltransferases. Loss of repressive histone modifications, such as H3K9me2/3, H3K27me2/3 and DNA methylation and demethylation may occur actively or passively through cell divisions. Histone acetylation also strongly increases transcriptional activity (b). The opposite route may lead to transcriptional silencing of differentiation genes during reprogramming towards pluripotency, or silencing of pluripotency genes during cell differentiation. The steps represented may occur simultaneously and/or in a different order according to the gene and system considered. The order of the epigenetic events that occur during nuclear reprogramming may not be in the exact reverse order of the events that occur during cell differentiation.
Mentions: As cells differentiate, their chromatin becomes increasingly condensed. Nuclear volume is indicative of the average extent of chromatin condensation. We estimate the volume of a nucleus (inversely related to condensation) in lymphocytes, non-mammalian red blood cells, and sperm, to be three, eight or 100 times respectively, smaller than that of an ES cell. In all nuclear transfer experiments, both in eggs and oocytes, a nuclear volume increase of 10–30-fold accompanies new gene transcripts [29], chromosomal proteins leave the nucleus and chromosomal protein mobility is increased [30]. Likewise, in heterokaryon experiments, similar changes follow cell fusion [6,7,31]. However, changes in nuclear volumes are not sufficient for gene reactivation because Polycomb-deficient ES cells do not induce pluripotency gene reactivation when fused to human B-lymphocytes but nuclear volume changes remain unperturbed [32]. In Figure 3, we present a hypothetical model of chromosomal changes associated with nuclear reprogramming.

Bottom Line: Transcription factors, chromatin modifications, and noncoding RNAs can increase the efficiency of reprogramming.However, the success of nuclear reprogramming is limited by epigenetic mechanisms that stabilise the state of gene expression in somatic cells and thereby resist efficient reprogramming.We see this as a step towards understanding the mechanisms by which nuclear reprogramming takes place.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.

Show MeSH