Alternative titles; symbols
HGNC Approved Gene Symbol: CBX5
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38) : 12:54,230,942-54,280,122 (from NCBI)
Heterochromatin protein-1 (HP1) is a methyl-lysine binding protein localized at heterochromatin sites. HP1 mediates gene silencing (summary by Bannister et al., 2001).
At the nuclear envelope in higher eukaryotic cells, the nuclear lamina and the heterochromatin are adjacent to the inner nuclear membrane. Using the nucleoplasmic N terminus of lamin B receptor (LBR; 600024), an integral protein of the inner nuclear membrane, as bait in a yeast 2-hybrid screen of a HeLa cell cDNA library, Ye and Worman (1996) isolated 2 chromodomain proteins that are homologs of Drosophila HP1. One of these proteins, CBX5, contains 191 amino acids and was previously cloned by Saunders et al. (1993). CBX5 shows 65% sequence similarity with the other identified protein, CBX3 (604477).
Maison et al. (2011) noted that HP1-alpha has an N-terminal chromodomain, followed by a hinge region and a C-terminal chromoshadow domain.
Ye and Worman (1996) found that LBR fusion proteins bound to CBX3 and CBX5 proteins synthesized by in vitro translation and present in cell lysates. LBR also coimmunoprecipitated the CBX proteins from cell extracts. Ye and Worman (1996) suggested that the interaction between LBR and the chromodomain proteins may explain, in part, the association of heterochromatin with the inner nuclear membrane.
Lachner et al. (2001) showed that mammalian methyltransferases that selectively methylate histone H3 (see 602810) on lysine-9 (Suv39h HMTases; see SUV39H1, 300254) generate a binding site for HP1 proteins, a family of heterochromatic adaptor molecules implicated in both gene silencing and supranucleosomal chromatin structure. High-affinity in vitro recognition of a methylated histone H3 peptide by HP1 requires a functional chromodomain; thus, the HP1 chromodomain is a specific interaction motif for the methyl epitope on lysine-9 of histone H3. In vivo, heterochromatin association of HP1 proteins is lost in Suv39h double-null primary mouse fibroblasts but is restored after reintroduction of a catalytically active SUV39H1 HMTase. Lachner et al. (2001) concluded that their data define a molecular mechanism through which the SUV39H-HP1 methylation system can contribute to the propagation of heterochromatic subdomains in native chromatin.
Bannister et al. (2001) demonstrated that HP1 can bind with high affinity to histone H3 methylated at lysine-9 but not at lysine-4. They identified the chromodomain of HP1 as its methyl-lysine-binding domain. A point mutation in the chromodomain, which destroys the gene silencing activity of HP1 in Drosophila, abolished methyl-lysine-binding activity. Genetic and biochemical analysis in S. pombe showed that the methylase activity of Clr4 (the SUV39H1 homolog) is necessary for the correct localization of Swi6 (the HP1 equivalent) at centromeric heterochromatin and for gene silencing. Bannister et al. (2001) concluded that these results provide a stepwise model for the formation of a transcriptionally silent heterochromatin: SUV39H1 places a methyl marker on histone H3, which is then recognized by HP1 through its chromodomain. This model may also explain the stable inheritance of the heterochromatic state.
Nielsen et al. (2001) demonstrated that SUV39H1 and HP1 are both involved in the repressive functions of the retinoblastoma protein (RB1; 614041). Rb1 associates with SUV39H1 and HP1 in vivo by means of its pocket domain. SUV39H1 cooperates with Rb to repress the cyclin E (123837) promoter, and in fibroblasts that are disrupted for SUV39H1, the activity of the cyclin E and cyclin A2 (123835) genes are specifically elevated. Chromatin immunoprecipitation showed that Rb is necessary to direct methylation of histone H3, and is necessary for binding of HP1 to the cyclin E promoter. Nielsen et al. (2001) concluded that the SUV39H1-HP1 complex is not only involved in heterochromatic silencing but also has a role in repression of euchromatic genes by Rb and perhaps other corepressor proteins.
Eukaryotic genomes are organized into discrete structural and functional chromatin domains. Noma et al. (2001) demonstrated that distinct site-specific histone H3 methylation patterns define euchromatic and heterochromatic chromosomal domains within an 47-kb region of the mating-type locus in fission yeast. H3 methylated at lysine-9, and its interacting Swi6 protein, are strictly localized to a 20-kb silent heterochromatic interval. In contrast, H3 methylated at lysine-4 is specific to the surrounding euchromatic regions. Two inverted repeats flanking the silent interval serve as boundary elements to mark the borders between heterochromatin and euchromatin. Deletions of these boundary elements leads to spreading of H3 lys9 methylation and Swi6 into neighboring sequences. Furthermore, the H3 lys6 methylation and corresponding heterochromatin-associated complexes prevent H3 lys4 methylation in the silent domain.
The higher-order assembly of chromatin imposes structural organization on the genetic information of eukaryotes and is thought to be largely determined by posttranslational modification of histone tails. Hall et al. (2002) studied a 20-kb silent domain at the mating-type region of S. pombe as a model for heterochromatin formation. They found that although histone H3 methylated at lys9 directly recruited heterochromatin protein Swi6/HP1, the critical determinant for H3 lys9 methylation to spread in cis to be inherited through mitosis and meiosis is Swi6 itself. The authors demonstrated that a centromere homologous repeat present at the silent mating-type region is sufficient for heterochromatin formation at an ectopic site, and that its repressive capacity is mediated by components of the RNA interference machinery. Moreover, the centromere homologous repeat and the RNA interference machinery cooperate to nucleate heterochromatin assembly at the endogenous mating locus but are dispensable for its subsequent inheritance. Hall et al. (2002) concluded that their work defines sequential requirements for the initiation and propagation of regional heterochromatic domains.
Cheutin et al. (2003) demonstrated that maintenance of stable heterochromatin domains in living cells involves the transient binding and dynamic exchange of HP1 from chromatin. HP1 exchange kinetics correlated with the condensation level of chromatin and were dependent on the histone methyltransferase SUV39H. The chromodomain and the chromoshadow domain of HP1 are both required for binding to native chromatin in vivo, but they contribute differentially to binding in euchromatin and heterochromatin. Cheutin et al. (2003) suggested that their data argue against HP1 repression of transcription by formation of static, higher order oligomeric networks but support a dynamic competition model, and demonstrate that heterochromatin is accessible to regulatory factors.
Chadwick and Willard (2003) screened over 30 histone variants, modified histones, and nonhistone proteins for their association with or exclusion from the Barr body. They demonstrated that HP1, histone H1 (HIST1H1B; 142711), and the high mobility group protein HMGIY (HMGA1; 600701) were elevated at the territory of the inactive X chromosome (Xi) in interphase in human cell lines, but only when the Xi chromatin was heteropycnotic, implicating each as a component of the Barr body. However, virtually all other candidate proteins involved in establishing heterochromatin and gene silencing were notably absent from the Barr body, suggesting that the Barr body may represent a discrete subnuclear compartment that is not freely accessible to most chromatin proteins. A similar dichotomous pattern of association or exclusion describes the spatial relationship of a number of specific histone methylation patterns in relation to the Barr body. The authors hypothesized that the Xi may adopt a distinct chromatin configuration in interphase nuclei, consistent with a mechanism by which HP1, through histone H3 (H3F2; 142780) lysine-9 methylation, recognizes and assists in maintaining heterochromatin and gene silencing at the human Xi.
Following overexpression of MIS12 (609178) in HeLa cells, Obuse et al. (2004) immunoprecipitated several proteins, including HP1-alpha, that interacted with MIS12 in a kinetochore-associated complex. Both HP1-alpha and HP1-gamma (CBX3) interacted directly with MIS12 and C20ORF172 (609175). Exclusion chromatography revealed 3 peaks containing MIS12 and C20ORF172, but only the middle peak, which had a mass of 669 kD, contained HP1-alpha. Using HP1 RNA interference (RNAi), Obuse et al. (2004) found that HP1-alpha and HP1-gamma were functionally redundant. In double HP1 RNAi, the integrity of kinetochores was abolished and micronuclei were formed. Obuse et al. (2004) hypothesized that the firm association of heterochromatic HP1 with the MIS12 complex may be a fundamental feature of human kinetochore formation.
Fischle et al. (2005) demonstrated that HP1-alpha, HP1-beta (604511), and HP1-gamma (604477) are released from chromatin during the M phase of the cell cycle even though trimethylation levels of histone H3 lys9 remain unchanged. However, the additional transient modification of histone H3 by phosphorylation of ser10 next to the more stable methyl-lys9 mark is sufficient to eject HP1 proteins from their binding sites. Inhibition or depletion of the mitotic kinase Aurora B (604970), which phosphorylates histone H3 on ser10, causes retention of HP1 proteins on mitotic chromosomes, suggesting that H3 ser10 phosphorylation is necessary for the dissociation of HP1 from chromatin in M phase. Fischle et al. (2005) concluded that their findings establish a regulatory mechanism of protein-protein interactions, through a combinatorial readout of 2 adjacent posttranslational modifications: a stable methylation and a dynamic phosphorylation mark.
Hirota et al. (2005) showed that antibodies against mitotic chromosomal antigens that are associated with human autoimmune diseases specifically recognize H3 molecules that are modified by both trimethylation of lys9 and phosphorylation of ser10 (H3K9me3S10ph). The generation of H3K9me3S10ph depends on Suv39h (see 300254) and Aurora B (604970), and occurs at pericentric heterochromatin during mitosis in different eukaryotes. Most HP1 typically dissociates from chromosomes during mitosis, but if phosphorylation of H3 ser10 is inhibited, HP1 remains chromosome-bound throughout mitosis. H3 phosphorylation by Aurora B is therefore part of a 'methyl/phos switch' mechanism that displaces HP1 and perhaps other proteins from mitotic heterochromatin.
Smallwood et al. (2007) demonstrated that DNMT1 (126375) could interact with HP1-alpha, HP1-beta, and HP1-gamma in a human colon carcinoma cell line, resulting in stimulation of DNMT1 methyltransferase activity. The HP1 proteins were sufficient to target DNMT1 activity in vivo, and HP1-dependent repression required DNMT1. Smallwood et al. (2007) demonstrated that HP1-alpha and HP1-beta were recruited to the survivin (BIRC5; 603352) promoter in a DNMT1-dependent manner. They concluded that direct interactions between HP1 proteins and DNMT1 mediate silencing of euchromatic genes.
Dawson et al. (2009) showed that human JAK2 (147796) is present in the nucleus of hematopoietic cells and directly phosphorylates tyr41 (Y41) on histone H3 (see 601128). HP1-alpha, but not HP1-beta, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukemic cells decreases both the expression of hematopoietic oncogene LMO2 (180385) and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1-alpha at the same site. Dawson et al. (2009) concluded that their results identified a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and revealed a direct mechanistic link between 2 genes, JAK2 and LMO2, involved in normal hematopoiesis and leukemia.
Hayashihara et al. (2010) found that a central region of HP1BP74 (HP1BP3; 616072) interacted directly with nucleosomes and with HP1. This fragment also protected DNA at nucleosome entry and exit sites from nuclease digestion. Full-length HP1BP74 also interacted with HP1. Mutation analysis showed that a PxVxL motif of HP1BP74 and trp174 within the chromo-shadow domain of HP1 were required for interaction.
Maison et al. (2011) found that mouse Hp1-alpha bound RNA that originated from the major satellite repeat region of mouse centromeres. Binding occurred predominantly with RNA transcribed in the forward orientation. Mutation analysis revealed that the hinge domain of Hp1-alpha was required for RNA binding. Mass spectrometry revealed that several lysines within the hinge region were modified by sumoylation and could accept Sumo1 (601912), Sumo2 (603042), or Sumo3 (602231). Sumoylation of Hp1-alpha was required for binding major RNAs, and RNA binding promoted targeting of Hp1-alpha to pericentric heterochromatin. Subsequent H3K9 methylation appeared to stabilize Hp1-alpha at pericentric heterochromatin.
The histone methylase SUV39H1 (300254) participates in the trimethylation of histone H3 on lysine-9 (H3K9me3; see 601128), a modification that provides binding sites for HP1-alpha and promotes transcriptional silencing. This pathway was initially associated with heterochromatin formation and maintenance but can also contribute to the regulation of euchromatic genes. Allan et al. (2012) proposed that the SUV39H1-H3K9me3-HP1-alpha pathway participates in maintaining the silencing of TH1 loci, ensuring TH2 lineage stability. In TH2 cells that are deficient in SUV39H1, the ratio between trimethylated and acetylated H3K9 is impaired, and the binding of HP1-alpha at the promoters of silenced TH1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient TH2 cells and HP1-alpha-deficient TH2 cells, in contrast to wildtype cells, expressed TH1 genes when recultured under conditions that drive differentiation into TH1 cells. In a mouse model of TH2-driven allergic asthma, the chemical inhibition or loss of SUV39H1 skewed T-cell responses towards TH1 responses and decreased the lung pathology.
Larson et al. (2017) identified the property of the human HP1-alpha protein to form phase-separated droplets. While unmodified HP1-alpha is soluble, either phosphorylation of its N-terminal extension or DNA binding promotes the formation of phase-separated droplets. Phosphorylation-driven phase separation can be promoted or reversed by specific HP1-alpha ligands. Known components of heterochromatin such as nucleosomes and DNA preferentially partition into the HP1-alpha droplets, but molecules such as the transcription factor TFIIB (189963) show no preference. Using a single-molecule DNA curtain assay, Larson et al. (2017) found that both unmodified and phosphorylated HP1-alpha induce rapid compaction of DNA strands into puncta, although with different characteristics. Larson et al. (2017) showed by direct protein delivery into mammalian cells that an HP1-alpha mutant incapable of phase separation in vitro forms smaller and fewer nuclear puncta than phosphorylated HP1-alpha. These findings suggested that heterochromatin-mediated gene silencing may occur in part through sequestration of compacted chromatin in phase-separated HP1 droplets, which are dissolved or formed by specific ligands on the basis of nuclear context.
Strom et al. (2017) demonstrated that Drosophila Hp1a protein undergoes liquid-liquid demixing in vitro, and nucleates into foci that display liquid properties during the first stages of heterochromatin domain formation in early Drosophila embryos. Furthermore, in both Drosophila and mammalian cells, heterochromatin domains exhibit dynamics that are characteristic of liquid phase separation, including sensitivity to the disruption of weak hydrophobic interactions, and reduced diffusion, increased coordinated movement, and inert probe exclusion at the domain boundary. Strom et al. (2017) concluded that heterochromatic domains form via phase separation, and mature into a structure that includes liquid and stable compartments.
Ostapcuk et al. (2018) showed that ADNP (611386) interacts with the chromatin remodeler CHD4 (603277) and the chromatin architectural protein HP1 to form a stable complex, which they referred to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. Genetic ablation of ChAHP components in mouse embryonic stem cells resulted in spontaneous differentiation concomitant with premature activation of lineage-specific genes and in a failure to differentiate towards the neuronal lineage. Molecularly, ChAHP-mediated repression is fundamentally different from canonical HP1-mediated silencing: HP1 proteins, in conjunction with H3K9me3, are thought to assemble broad heterochromatin domains that are refractory to transcription. ChAHP-mediated repression, however, acts in a locally restricted manner by establishing inaccessible chromatin around its DNA-binding sites and does not depend on H3K9me3-modified nucleosomes. Ostapcuk et al. (2018) concluded that their results revealed that ADNP, via the recruitment of HP1 and CHD4, regulates the expression of genes that are crucial for maintaining distinct cellular states and assures accurate cell fate decisions upon external cues. Such a general role of ChAHP in governing cell fate plasticity may explain why ADNP mutations affect several organs and body functions and contribute to cancer progression. Ostapcuk et al. (2018) found that the integrity of the ChAHP complex is disrupted by nonsense mutations identified in patients with Helsmoortel-Van der Aa syndrome (615873), and this could be rescued by aminoglycosides that suppress translation termination.
Zhang et al. (2019) developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded GGGGCC (G4C2) repeats in C9ORF72 (614260), which result in frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS1; 105550). The expression of green fluorescent protein-conjugated (PR)50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. Zhang et al. (2019) found that poly(PR) bound DNA, localized to heterochromatin, and caused HP1a liquid-phase disruptions, decreases in HP1a expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Zhang et al. (2019) concluded that they uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS.
The International Radiation Mapping Consortium mapped the CBX5 gene to chromosome 12 (STS-Z40708).
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