A specific interest is taken in the pluripotency master regulator, Oct4. Neuronal differentiation of ESCs results in a gradual removal of these marks, H3K4me2 being the last mark to persist until the fully differentiated state, albeit at low levels [ 30 ].
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Nanog and Tcl1 are two additional important self-renewal factors in ESCs, downstream targets of Oct4. In our recent attempt to delineate the mechanisms that underlay chromatin plasticity regulation in ESCs S. Meshorer, unpublished work , we examined the effects of both histone acetylation and methylation on chromatin protein dynamics. Additionally, when comparing spontaneous differentiation levels, hyperacetylated ESCs retained their pluripotency, and spontaneous differentiation was inhibited more than 2-fold over normally acetylated ESCs.
In contrast, HDAC inhibitors augmented neuronal differentiation in NPCs, suggesting that an epigenetic barrier exists early during ESC differentiation after which differentiation cannot be prevented by increasing histone acetylation. Thus histone acetylation affects chromatin plasticity in differentiated cells, in pluripotent cells and in multipotent lineage-committed cells, subsequently affecting their propensity to differentiate, albeit in a differentiation-stage-dependent manner. Histone methylation also plays important roles in regulating chromatin plasticity in ESCs. This effect was prominent in heterochromatin foci and hardly seen in euchromatin.
Adding G9a back into the mutant ESCs fully restored neuronal differentiation capacity as well as wild-type chromatin protein dynamics throughout differentiation. Thus histone methylation in heterochromatin is at least partly responsible for chromatin restriction in differentiating ESCs, which is evidently required for proper differentiation. These findings demonstrate further the function of chromatin plasticity in maintaining pluripotency, commencing and completing differentiation, and it appears that a unique pattern of certain histone modifications is the basis of this crucial chromatin state.
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Chromatin marks, on both histones and DNA, act as binding or recognition sites for various chromatin-remodelling proteins; these are characterized by ATPase domains, chromodomains, bromodomains and different binding motifs that recruit other participants in chromatin marking or structuring [ 3 , 52 , 53 ].
Another good example of this histone-code—chromatin-remodelling network is the H3K4me3-recruited Chd1 chromodomain-helicase-DNA-binding protein 1 , which seems to regulate both chromatin plasticity and pluripotency in ESCs [ 63 ]. In Chd1-deficient ESCs, heterochromatin is more prevalent, and chromatin protein dynamics are reduced in euchromatic regions, implicating Chd1 as a chromatin remodeller that participates in maintaining an open-chromatin formation in undifferentiated ESCs.
Without Chd1, ESCs are not truly pluripotent; they are prone to neural-lineage ectoderm differentiation and do not give rise to primitive endoderm [ 63 ]. This combination of active and repressive histone marks accompanied by antagonist chromatin-associated proteins provides a reasonable explanation for pluripotent-related chromatin plasticity. A spectrum of chromatin-associated proteins with opposite architectural functions is recruited by apparently incoherent signals to a wide variety of regulatory junctions in the genome.
This results in multiple gene loci that are primed for transcription, rendering chromatin highly plastic and hyperdynamic, but without the subsequent multitude of expression products one would expect from over-transcriptional activity. Lamins are type V IFs intermediate filaments that comprise the nuclear lamina, a proteinaceous meshwork underlining the INM inner nuclear membrane of the nuclear envelope. Lamins have a wide network of interactions with other lamins, INM proteins, transcription factors, chromatin and DNA and they are known to have a role in a large variety of nuclear processes [ 64 ].
Lamins are divided into two groups: A- and B-type. Several clues point to a connection between lamin A and chromatin plasticity regulation in differentiating cells. First, whereas B-type lamins are expressed in all cells throughout development, A-type lamins are not detected in ESCs, but only in early differentiating cells, at the stage when chromatin proteins become immobile [ 64 , 66 ]. These differences in lamina structure apparently have a mechanical effect on the nuclear envelope; differentiating cell nuclei are more rigid and less prone to deformation than ESC nuclei that exhibit not only high chromatin plasticity, but also high physical plasticity [ 67 ].
Secondly, lamin A was shown to bind DNA and chromatin [ 68 — 70 ], and specific conserved sequences in Drosophila and Caenorhabditis elegans were shown to specifically bind histone H2A [ 71 ]. Considering the above evidence, lamin A may serve as an additional player controlling chromatin plasticity by restricting chromatin dynamics upon early differentiation.
We found that lamin A significantly restricts chromatin protein dynamics, exclusively in heterochromatin regions, when ectopically expressed in wild-type ESCs. The repressive mark H3K27me3, which is adjacent to the nuclear envelope in undifferentiated ESCs, is reduced and is redistributed upon differentiation and concomitant expression of lamin A. Although the connection between lamin A expression and H3K27me3 de-localization might be circumstantial, it does join evidence regarding lamina plasticity loss and overall nuclear stiffening, including chromatin structure [ 29 , 67 ], raising the possibility that certain gene-regulation mechanisms react to acute changes in plasticity.
Lamin A is generally associated with nuclear structural and functional integrity and takes part in many nuclear processes. As such, it is a difficult task to specifically link it with just one of its many roles in proper cell development and function, including chromatin plasticity, in the light of pleiotropic effects. Nevertheless, there is a considerable variety of evidence from different sources, independently implicating lamin A, specifically, as a chromatin plasticity regulator. Our work suggests that it would be a challenging task to further fine-tune the elucidation of this regulatory function.
As we have seen, chromatin in ESCs is distinct from that of differentiated and somatic cells in many respects. It seems that the unique properties featured in ESC chromatin mostly contribute to its plastic state regulating ESC pluripotency, self-renewal capacity and differentiation potential. Since ESCs hold great promise for degenerative diseases and cell-based therapy, it is essential to understand the basic mechanisms that make ESCs what they are in order to manipulate ESCs intelligently and safely and facilitate their use in the clinic.
Since chromatin is the basic scaffold for genetic stability, genetic and epigenetic inheritance, gene expression and regulation and cell-cycle progression, understanding chromatin plasticity in ESCs is key to understanding pluripotency and ESC function. Recent advances in high-throughput technologies, such as massively parallel sequencing and multi-dimensional proteomics, will enable rapid profiling of epigenetic states in ESCs and efficient identification of molecules that regulate chromatin in ESCs. Once the basic biology is understood, it will lay the ground to take the extra necessary step towards the clinic.
Undifferentiated ESCs display a global promiscuous transcriptional programme which is restricted gradually upon differentiation. ESC differentiation is characterized by substantial changes, including, i reduction in chromatin plasticity, exhibited as structural condensation and restriction of chromatin protein dynamics; ii significant changes in chromatin modifications, including histone marks and DNA methylation; and iii changes in nuclear architecture.
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Jan Postberg. Dean A. Previous Article Next Article. Transcription profiles of pluripotent compared with differentiated cells. Chromatin plasticity in pluripotent cells. Epigenetic effectors of chromatin plasticity. Review Article September 20 Chromatin plasticity in pluripotent cells Shai Melcer Shai Melcer. Eran Meshorer Eran Meshorer. Essays Biochem Split-Screen Views Icon Views. Get Permissions. Figure 1.
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Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Induced pluripotent stem cells: current progress and potential for regenerative medicine. A chromatin landmark and transcription initiation at most promoters in human cells. Design principle of gene expression used by human stem cells: implication for pluripotency. Multilineage gene expression precedes commitment in the hemopoietic system.
Gene expression analysis of purified hematopoietic stem cells and committed progenitors.