Zinc finger proteins orchestrate active gene silencing during embryonic stem cell differentiation
Sojung KwakTae Wan KimByung Hee KangJae-Hwan KimJang-Seok LeeHan‐Teo LeeIn‐Young HwangJihoon ShinJong‐Hyuk LeeEun‐Jung ChoHong‐Duk Youn
23
Citation
67
Reference
10
Related Paper
Citation Trend
Abstract:
Transcription factors and chromatin remodeling proteins control the transcriptional variability for ESC lineage commitment. During ESC differentiation, chromatin modifiers are recruited to the regulatory regions by transcription factors, thereby activating the lineage-specific genes or silencing the transcription of active ESC genes. However, the underlying mechanisms that link transcription factors to exit from pluripotency are yet to be identified. In this study, we show that the Ctbp2-interacting zinc finger proteins, Zfp217 and Zfp516, function as linkers for the chromatin regulators during ESC differentiation. CRISPR-Cas9-mediated knock-outs of both Zfp217 and Zfp516 in ESCs prevent the exit from pluripotency. Both zinc finger proteins regulate the Ctbp2-mediated recruitment of the NuRD complex and polycomb repressive complex 2 (PRC2) to active ESC genes, subsequently switching the H3K27ac to H3K27me3 during ESC differentiation for active gene silencing. We therefore suggest that some zinc finger proteins orchestrate to control the concise epigenetic states on active ESC genes during differentiation, resulting in natural lineage commitment.Keywords:
Polycomb-group proteins
Bivalent chromatin
Chromatin structure has a pivotal role in the regulation of gene expression. Transcriptional activation or the repression of a gene require the recruitment of multiple chromatin remodeling complexes. Chromatin remodeling complexes modulate the higher order structure of chromatin, facilitate or hinder the binding of transcription factors, and aid in or prevent the establishment of a transcriptional preinitiation complex. Two types of chromatin remodeling complexes have been extensively studied — ATP-dependent chromatin remodeling complexes and histone-modifying enzymes — which include histone acetyltransferases, histone deacetylases, and histone kinases. Transcriptional activators and repressors are responsible for recruitment of one or more of these large, multisubunit chromatin remodeling complexes. In this review, the features of the chromatin remodeling complexes and the modes of their recruitment are presented.
Histone-modifying enzymes
Bivalent chromatin
ChIA-PET
Histone code
Cite
Citations (36)
Bivalent chromatin
ChIA-PET
Scaffold/matrix attachment region
Histone-modifying enzymes
Cite
Citations (61)
Chromatin structure has a pivotal role in the regulation of gene expression. Transcriptional activation or the repression of a gene require the recruitment of multiple chromatin remodeling complexes. Chromatin remodeling complexes modulate the higher order structure of chromatin, facilitate or hinder the binding of transcription factors, and aid in or prevent the establishment of a transcriptional preinitiation complex. Two types of chromatin remodeling complexes have been extensively studied ATP-dependent chromatin remodeling complexes and histone-modifying enzymes which include histone acetyltransferases, histone deacetylases, and histone kinases. Transcriptional activators and repressors are responsible for recruitment of one or more of these large, multisubunit chromatin remodeling complexes. In this review, the features of the chromatin remodeling complexes and the modes of their recruitment are presented.
Histone-modifying enzymes
Bivalent chromatin
ChIA-PET
Histone code
Cite
Citations (2)
Chromatin provides both a means to accommodate a large amount of genetic material in a small space and a means to package the same genetic material in different chromatin states. Transitions between chromatin states are enabled by chromatin-remodeling ATPases, which catalyze a diverse range of structural transformations. Biochemical evidence over the last two decades suggests that chromatin-remodeling activities may have emerged by adaptation of ancient DNA translocases to respond to specific features of chromatin. Here, we discuss such evidence and also relate mechanistic insights to our understanding of how chromatin-remodeling enzymes enable different in vivo processes. Chromatin provides both a means to accommodate a large amount of genetic material in a small space and a means to package the same genetic material in different chromatin states. Transitions between chromatin states are enabled by chromatin-remodeling ATPases, which catalyze a diverse range of structural transformations. Biochemical evidence over the last two decades suggests that chromatin-remodeling activities may have emerged by adaptation of ancient DNA translocases to respond to specific features of chromatin. Here, we discuss such evidence and also relate mechanistic insights to our understanding of how chromatin-remodeling enzymes enable different in vivo processes.
Cite
Citations (599)
The development of a metazoan from a single-celled zygote to a complex multicellular organism requires elaborate and carefully regulated programs of gene expression. However, the tight packaging of genomic DNA into chromatin makes genes inaccessible to the cellular machinery and must be overcome by the processes of chromatin remodeling; in addition, chromatin remodeling can preferentially silence genes when their expression is not required. One class of chromatin remodelers, ATP-dependent chromatin-remodeling enzymes, can slide nucleosomes along the DNA to make specific DNA sequences accessible or inaccessible to regulators at a particular stage of development. While all ATPases in the SWI2/SNF2 superfamily share the fundamental ability to alter DNA accessibility in chromatin, they do not act alone, but rather, are subunits of a large assortment of protein complexes. Recent studies illuminate common themes by which the subunit compositions of chromatin-remodeling complexes specify the developmental roles that chromatin remodelers play in specific tissues and at specific stages of development, in response to specific signaling pathways and transcription factors. In this review, we will discuss the known roles in metazoan development of 3 major subfamilies of chromatin-remodeling complexes: the SNF2, ISWI, and CHD subfamilies.
Bivalent chromatin
ChIA-PET
Multicellular organism
Histone-modifying enzymes
Scaffold/matrix attachment region
Cite
Citations (27)
Abstract The dynamic changes in chromatin conformation alter the organization and structure of the genome and further regulate gene transcription. Basically, the chromatin structure is controlled by reversible, enzyme-catalyzed covalent modifications to chromatin components and by noncovalent ATP-dependent modifications via chromatin remodeling complexes, including switch/sucrose nonfermentable (SWI/SNF), inositol-requiring 80 (INO80), imitation switch (ISWI) and chromodomain-helicase DNA-binding protein (CHD) complexes. Recent studies have shown that chromatin remodeling is essential in different stages of postnatal and adult neurogenesis. Chromatin deregulation, which leads to defects in epigenetic gene regulation and further pathological gene expression programs, often causes a wide range of pathologies. This review first gives an overview of the regulatory mechanisms of chromatin remodeling. We then focus mainly on discussing the physiological functions of chromatin remodeling, particularly histone and DNA modifications and the four classes of ATP-dependent chromatin-remodeling enzymes, in the central and peripheral nervous systems under healthy and pathological conditions, that is, in neurodegenerative disorders. Finally, we provide an update on the development of potent and selective small molecule modulators targeting various chromatin-modifying proteins commonly associated with neurodegenerative diseases and their potential clinical applications.
Cite
Citations (29)
AbstractThe fate of the cell relies on a delicate balance between gene expression and repression. The transcriptional control of the genome is maintained not only by transcription factors but also chromatin remodeling proteins. The purpose of the chromatin remodeling proteins is to alter the nucleosome architecture such that genes are exposed to or hidden from the transcriptional machinery. The nucleosome can be restructured by two mechanisms: 1. the movement of nucleosomes along DNA which is carried out by ATP-dependent chromatin remodeling complexes; and 2. the modification of core histones by histone acetyltransferases, deactylases, methyltransferases, and kinases. Since these chromatin remodeling proteins play an essential role in transcriptional regulation, it is not surprising that they have been linked to cancer. In this review, we provide a general overview on chromatin remodeling and describe known genetic alterations of chromatin remodeling proteins in human cancers. We also discuss potential other, as yet unexplored strategies that cancers might take to manipulate the chromatin remodeling machinery.
Histone-modifying enzymes
Bivalent chromatin
ChIA-PET
Chromodomain
SWI/SNF
Cite
Citations (106)
Abstract Chromatin states profoundly determine and maintain gene activity and gene repression in eukaryotic organisms. Regulation of chromatin involves chromatin remodeling, chromatin modifications and exchange of chromatin components and is linked to DNA methylation in some cases. In plants and other organisms, chromatin proteins control many developmental pathways, integrate changes in the environment and can confer a cellular memory of these cues. Here, we review the molecular mechanisms that provide a dynamic regulation of chromatin in a cell. In addition, we discuss how chromatin needs to be flexibly regulated during plant growth to confer stable expression states that can occasionally be reset, e.g., owing to changes in the environment and progression of development.
Bivalent chromatin
Histone-modifying enzymes
ChIA-PET
Cite
Citations (11)
The PHO5 and PHO8 genes in yeast provide typical examples for the role of chromatin in promoter regulation. Both genes are regulated by the same transcriptional activator, Pho4, which initiates nucleosome remodeling and transcriptional activation. In spite of this co-regulation, there are important differences in gene activity and in the way promoter chromatin undergoes chromatin remodeling. First, PHO5 belongs to one of the most strongly induced genes in yeast being 10-fold more active than the PHO8 gene (Oshima, 1997; Barbaric et al., 1992). Second, chromatin remodeling at the PHO5 promoter affects four nucleosomes (Almer et al., 1986), whereas only two nucleosomes are afffected at the PHO8 promoter (Barbaric et al., 1992). Third, neither the histone acetyl transferase Gcn5 nor chromatin remodeling complex Swi/Snf seem to be critically required for chromatin remodeling at the PHO5 promoter (Barbaric et al., 2001; Reinke and Horz, 2003; Dhasarathy and Kladde, 2005; Neef and Kladde, 2003). At the PHO8 promoter, on the other hand, absence of Swi/Snf results in the complete loss of chromatin remodeling under inducing conditions. Furthermore, Gcn5 is required for full remodeling and transcriptional activation at this promoter (Gregory et al., 1999).
Ever since these differences were recognized there have been speculations about the underlying reasons. This work shows that these discrepancies are not a direct consequence of the position or strength of the UASp elements driving the activation of transcription. Instead, these differences result from different stabilities of the two promoter chromatin structures. The basis for these results was the development of a competitive yeast in vitro assembly technique in which differences in nucleosome stability between promoter regions could be directly compared. This technique originated from a yeast in vitro chromatin assembly system that generated the characteristic PHO5 promoter chromatin structre (Korber and Horz, 2004). As shown here, this system also assembles the native PHO8 promoter nucleosome pattern. Using the competitive assembly system it was shown that the PHO8 promoter has greater nucleosome positioning power, and that the properly positioned nucleosomes are more stable than at the PHO5 promoter. This provided for the first time evidence for the correlation of inherently more stable chromatin with stricter co-factor requirements.
Remarkably, the positioning information for the in vitro assembly of the native PHO5 and PHO8 promoter chromatin patterns was specific to the yeast extract. Salt gradient dialysis or Drosophila embryo extract assemblies did not support the proper nucleosome positioning.
However, nucleosomes in chromatin generated in these systems could be shifted to their in vivo-like positions by the addition of yeast extract. This indicates that the nucleosome positioning mechanisms in vitro are uncoupled from the nucleosome loading machinery. The nucleosome positioning at the PHO5 and PHO8 promoters was energy dependent suggesting a role of chromatin remodeling machines in generation of the repressed promoter chromatin structure. In spite of this, the chromatin remodeling machines Swi/Snf, Isw1, Isw2 and Chd1 were dispensable nucleosome positioning at both promoters.
ChIA-PET
Bivalent chromatin
SWI/SNF
Transcription
Cite
Citations (0)
Bivalent chromatin
ChIA-PET
Cite
Citations (74)