Chromo-domain proteins: linking chromatin structure to epigenetic regulation

doi:10.1016/S0955-0674(98)80011-2

Current Opinion in Cell Biology

Volume 10, Issue 3, June 1998, Pages 354-360

https://doi.org/10.1016/S0955-0674(98)80011-2 Get rights and content

Abstract

Chromo-domain proteins appear to be a central component in the epigenetic regulation of heterochromatin function and euchromatic gene expression. The recent discovery of a variety of interacting partners of chromo-domain proteins is yielding new molecular insights into epigenetic regulatory processes acting at the level of higher order chromatin structure.

References (37)

F Cleard et al.
SU(VAR)3–7, a Drosophila heterochromatin-associated protein and companion of HP1 in the genomic silencing of position-effect variegation
EMBO J
(1997)
KE Brown et al.
Association of transcriptionally silent genes with ikaros complexes at centromeric heterochromatin
Cell
(1997)
I Callebaut et al.
Hydrophobic cluster analysis reveals a third chromo domain in the Tetrahymena Pdd1p protein of the chromo superfamily
Biochem Biophys Res Commun
(1997)
A Busturia et al.
Silencers in abdominal-B, a homeotic Drosophila gene
EMBO J
(1993)
CS Chan et al.
A Polycomb response element in the Ubx gene that determines an epigenetically inherited state of repression
EMBO J
(1994)
D Zink et al.
Drosophila Polycomb-group regulated chromatin inhibits the accessibility of a trans-activator to its target DNA
EMBO J
(1995)
R Paro et al.
The Polycomb protein shares a homologous domain with a heterochromatin-associated protein of Drosophila
Proc Natl Acad Sci USA
(1991)
JC Eissenberg et al.
Mutation in a heterochromatin-specific chromosomal protein is associated with suppression of position-effect variegation in Drosophila melanogaster
Proc Natl Acad Sci USA
(1990)
R Paro et al.
The role of Polycomb group and trithorax group chromatin complexes in the maintenance of determined cell states
N Core et al.
Altered cellular proliferation and mesoderm patterning in Polycomb M33 deficient mice
Development
(1997)

EV Koonin et al.

The chromo superfamily: new members, duplication of the chromo domain and possible role in delivering transcription regulators to chromatin

Nucleic Acids Res

(1995)

R Aasland et al.

The chromo shadow domain, a second chromo domain in heterochromatin-binding protein 1, HP1

Nucleic Acids Res

(1995)

WS Saunders et al.

Molecular cloning of a human homologue of Drosophila heterochromatin protein HP1 using anti-centromere autoantibodies with anti-chromo specificity

J Cell Sci

(1993)

L Nicol et al.

Human autoimmune sera recognize a conserved 26 kD protein associated with mammalian heterochromatin that is homologous to heterochromatin protein 1 of Drosophila

Chrom Res

(1994)

LJ Ball et al.

Structure of the chromatin binding (chromo) domain from mouse modifier protein 1

EMBO J

(1997)

MJ Alkema et al.

Identification of Bmi1 interacting proteins as constituents of a multimeric mammalian Polycomb complex

Genes Dev

(1997)

H Strutt et al.

The Polycomb group protein complex of Drosophila melanogaster has different compositions at different target genes

Mol Cell Biol

(1997)

JS Platero et al.

Functional analysis of the chromo domain of HP1

EMBO J

(1995)

Cited by (154)

M33 condenses chromatin through nuclear body formation and methylation of both histone H3 lysine 9 and lysine 27
2021, Biochimica et Biophysica Acta - Molecular Cell Research
Heterochromatin, a type of condensed DNA in eukaryotic cells, has two main categories: Constitutive heterochromatin, which contains H3K9 methylation, and facultative heterochromatin, which contains H3K27 methylation. Methylated H3K9 and H3K27 serve as docking sites for chromodomain-containing proteins that compact chromatin. M33 (also known as CBX2) is a chromodomain-containing protein that binds H3K27me3 and compacts chromatin in vitro. However, whether M33 mediates chromatin compaction in cellulo remains unknown. Here we show that M33 compacts chromatin into DAPI-intense heterochromatin domains in cells. The formation of these heterochromatin domains requires H3K27me3, which recruits M33 to form nuclear bodies. G9a and SUV39H1 are sequentially recruited into M33 nuclear bodies to create H3K9 methylated chromatin in a process that is independent of HP1α. Finally, M33 decreases progerin-induced nuclear envelope disruption caused by loss of heterochromatin. Our findings demonstrate that M33 mediates the formation of condensed chromatin by forming nuclear bodies containing both H3K27me3 and H3K9me3. Our model of M33-dependent chromatin condensation suggests H3K27 methylation corroborates with H3K9 methylation during the formation of facultative heterochromatin and provides the theoretical basis for developing novel therapies to treat heterochromatin-related diseases.
Polycomb YY1 is a critical interface between epigenetic code and miRNA machinery after exposure to hypoxia in malignancy
2015, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
YY1 is associated with both complexes [12] and it is the only PcG protein with a sequence-specific DNA binding element (CCATnTT) and RNA binding properties [13]. Although, YY1 is mainly described as a transcription factor [13], the association between YY1 and PRC1/2 provides a direct link between the chromatin-PcG complex and the DNA of target genes [14]. YY1 has been shown to be involved in the development and/or progression of several solid and hematological tumors by interacting with cell cycle regulation.
Yin Yang 1 (YY1) is a member of polycomb protein family involved in epigenetic modifications and transcriptional controls. We have shown that YY1 acts as positive regulator of tumor growth and angiogenesis by interfering with the VEGFA network. Yet, the link between polycomb chromatin complex and hypoxia regulation of VEGFA is still poorly understood. Here, we establish that hypoxia impairs YY1 binding to VEGFA mRNA 3′UTR (p < 0.001) in bone malignancy. Moreover, RNA immunoprecipitation reveals the formation of triplex nuclear complexes among YY1, VEGFA DNA, mRNA, and unreached about 200 fold primiRNA 200b and 200c via Dicer protein. In this complex, YY1 is necessary to maintain the steady-state level of VEGFA expression while its silencing increases VEGFA mRNA half-life at 4 h and impairs the maturation of miRNA 200b/c. Hypoxia promotes histone modification through ubiquitination both of YY1 and Dicer proteins. Hypoxia-mediated down-regulation of YY1 and Dicer changes post-transcriptional VEGFA regulation by resulting in the accumulation of primiRNA200b/c in comparison to mature miRNAs (p < 0.001). Given the regulatory functions of VEGFA on cellular activities to promote neoangiogenesis, we conclude that YY1 acts as novel critical interface between epigenetic code and miRNAs machinery under chronic hypoxia in malignancy.
Genetics of gastrointestinal atresias
2014, European Journal of Medical Genetics
Citation Excerpt :
A role in epigenetic regulation has been proposed for this gene. It has been hypothesized that the CHD family could prevent changes of the epigenetic state of the chromatin fibers (Cavalli and Paro, 1998). CHD7 mutations have been found to cause most cases of CHARGE syndrome (MIM: 214800).
Gastrointestinal atresias are a common and serious feature within the spectrum of gastrointestinal malformations. Atresias tend to be lethal, although, now-days surgery and appropriate care can restore function to the affected organs. In spite of their frequency, their life threatening condition and report history gastrointestinal atresias' etiology remains mostly unclarified. Gastrointestinal atresias can occur as sporadic but they are more commonly seen in association with other anomalies. For the syndromic cases there is mounting evidence of a strong genetic component. Sporadic cases are generally thought to originate from mechanical or vascular incidents in utero, especially for the atresias of the lower intestinal tract. However, recent data show that a genetic component may be present also in these cases. Embryological and genetic studies are starting to uncover the mechanism of gastrointestinal development and their genetic components. Here we present an overview of the current knowledge of gastrointestinal atresias, their syndromic forms and the genetic pathways involved in gastrointestinal malformation.
EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex
2012, Molecular Cell
Ubiquitination plays a major role in protein degradation. Although phosphorylation-dependent ubiquitination is well known for the regulation of protein stability, methylation-dependent ubiquitination machinery has not been characterized. Here, we provide evidence that methylation-dependent ubiquitination is carried out by damage-specific DNA binding protein 1 (DDB1)/cullin4 (CUL4) E3 ubiquitin ligase complex and a DDB1-CUL4-associated factor 1 (DCAF1) adaptor, which recognizes monomethylated substrates. Molecular modeling and binding affinity studies reveal that the putative chromo domain of DCAF1 directly recognizes monomethylated substrates, whereas critical binding pocket mutations of the DCAF1 chromo domain ablated the binding from the monomethylated substrates. Further, we discovered that enhancer of zeste homolog 2 (EZH2) methyltransferase has distinct substrate specificities for histone H3K27 and nonhistones exemplified by an orphan nuclear receptor, RORα. We propose that EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing “methyl degron”; through this, nonhistone protein stability can be dynamically regulated in a methylation-dependent manner.
Structures of 5'-3' Exoribonucleases
2012, Enzymes
Citation Excerpt :
The remaining ∼ 510-residue segment at the C-terminal region of both structures is composed of four separate domains (named D1–D4, Fig. 6.1A). Domains D1, D2, and D4 share a common backbone fold, with a five-stranded β-barrel core, which is similar to that of Tudor, PAZ, chromo, KOW, or SH3-like domains (Fig. 6.3A–C) [17–20]. Most of these domains are involved in protein–protein, protein–peptide, or protein–nucleic acid interactions [21–23].
5′–3′ Exoribonucleases (XRNs) have important functions in RNA processing, RNA turnover and decay, RNA interference, RNA polymerase transcription, and other cellular processes. Their sequences share two highly conserved regions, CR1 and CR2. The cytoplasmic Xrn1 and the nuclear Xrn2/Rat1 are found in yeast and animals, and XRNs are found in most other eukaryotes. Crystal structures of Xrn1 and Rat1 have been reported recently, offering the first detailed information on these enzymes. The two conserved regions of XRNs form a single, large domain. CR1 has structural homology with the FEN superfamily of nucleases, while CR2 restricts access to the active site, ensuring that XRNs are exclusive exoribonucleases. The structure of Rai1, the protein partner of Rat1, revealed the presence of an active site, and further studies demonstrated that this activity is a novel mechanism for mRNA 5′-end capping quality surveillance.
Loss of the chromatin regulator MRG15 limits neural stem/progenitor cell proliferation via increased expression of the p21 Cdk inhibitor
2011, Stem Cell Research
Chromatin regulation is crucial for many biological processes such as transcriptional regulation, DNA replication, and DNA damage repair. We have found that it is also important for neural stem/progenitor cell (NSC) function and neurogenesis. Here, we demonstrate that expression of the cyclin-dependent kinase inhibitor p21 is specifically up-regulated in Mrg15 deficient NSCs. Knockdown of p21 expression by p21 shRNA results in restoration of cell proliferation. This indicates that p21 is directly involved in the growth defects observed in Mrg15 deficient NSCs. Activated p53 accumulates in Mrg15 deficient NSCs and this most likely accounts for the up-regulation of p21 expression in the cells. We observed decreased p53 and p21 levels and a concomitant increase in the percentage of BrdU positive cells in Mrg15 null cultures following expression of p53 shRNA. DNA damage foci, as indicated by immunostaining for γH2AX and 53BP1, are detectable in a sub-population of Mrg15 deficient NSC cultures under normal growing conditions and the majority of p21-positive cells are also positive for 53BP1 foci. Furthermore, Mrg15 deficient NSCs exhibit severe defects in DNA damage response following ionizing radiation. Our observations highlight the importance of chromatin regulation and DNA damage response in NSC function and maintenance.

View all citing articles on Scopus

View full text

Chromo-domain proteins: linking chromatin structure to epigenetic regulation

Abstract

EMBO J

Cell

Biochem Biophys Res Commun

EMBO J

EMBO J

EMBO J

The Polycomb protein shares a homologous domain with a heterochromatin-associated protein of Drosophila

Proc Natl Acad Sci USA

Mutation in a heterochromatin-specific chromosomal protein is associated with suppression of position-effect variegation in Drosophila melanogaster

Proc Natl Acad Sci USA

The role of Polycomb group and trithorax group chromatin complexes in the maintenance of determined cell states

Altered cellular proliferation and mesoderm patterning in Polycomb M33 deficient mice

Development

The chromo superfamily: new members, duplication of the chromo domain and possible role in delivering transcription regulators to chromatin

Nucleic Acids Res

The chromo shadow domain, a second chromo domain in heterochromatin-binding protein 1, HP1

Nucleic Acids Res

Molecular cloning of a human homologue of Drosophila heterochromatin protein HP1 using anti-centromere autoantibodies with anti-chromo specificity

J Cell Sci

Human autoimmune sera recognize a conserved 26 kD protein associated with mammalian heterochromatin that is homologous to heterochromatin protein 1 of Drosophila

Chrom Res

Structure of the chromatin binding (chromo) domain from mouse modifier protein 1

EMBO J

Identification of Bmi1 interacting proteins as constituents of a multimeric mammalian Polycomb complex

Genes Dev

The Polycomb group protein complex of Drosophila melanogaster has different compositions at different target genes

Mol Cell Biol

Functional analysis of the chromo domain of HP1

EMBO J