The centromere is a very specific part of the chromosome. When you look at the chromosomes, there's a part that is not always right in the middle, but it's somewhere between one-third and two-thirds of the way down the chromosome. It's called the centromere. That's the part where the cell's chromosomes are constricted, and they're a little bit tighter, and it almost looks like a little ball in the middle of two sticks.
The centromere is what separates the chromosome into what we call, for human chromosomes, the P and Q arm. And these P and Q arms are a part of what we use when we do cytogenetics to say how many chromosomes are present in a cell and what chromosome number they are. The positive or negative signs indicate whether the modification underlies transcriptional silence or activity, respectively. See text for explanations.
H4 mono-methylation at Lys20, which marks human and chicken CENP-A nucleosomes, and is associated with transcriptional activation, is a prerequisite for kinetochore assembly Sullivan and Karpen, ; Vakoc et al. Although electron microscopy-based studies had localized RNA at kinetochores in union and salamander cells in the s Braselton, ; Rieder, , CEN were long considered transcriptionally silent since they are confined in transcriptionally inert heterochromatin.
Cbf1 promotes transcription from the sense strand, Ste12 from the antisense strand. Silencing protein Dig1 inhibits Ste This phenotype was rescued by driving CEN transcription from an inducible promoter introduced next to the Cbf1- or Stebinding site, illustrating that CEN transcription is imperative for kinetochore activity Ohkuni and Kitagawa, CEN transcripts in S.
This approach revealed a 1. Low-level CEN transcription is required for kinetochore activity in budding yeast. Following glucose addition, the sisters bi-oriented on the metaphase spindle Tanaka et al.
This concurrence could be the result of selection pressure to preserve the transcription activity of this satellite DNA. TATA-box-like motifs, multiple transcription initiation and termination sites were also mapped within the monomer. It is unclear whether CEN transcription is downregulated during this process. Kinetochores then reassemble to attach the still-replicating chromatids to the interphase spindle Kitamura et al. In Drosophila , CEN transcription and chromatin remodeling are required for CENP-A to transition from an unstable chromatin-associated state to a stable nucleosome-incorporated state Bobkov et al.
In HACs containing engineered tetO operator sequences within the alpha-satellite DNA, and cells expressing transcriptional activators or silencers fused with the tetO-binding TetR protein both destabilized kinetochore formation Bergmann et al.
A loss or hyperphosphorylation of both sites causes chromosome missegregation Bailey et al. Mutations in Ser7, Ser16, and Ser18 sites lead to chromosome missegregation, abnormal spindles, and errors in cytokinesis Srivastava et al.
Centromere transcription dynamics through the cell cycle have only been studied recently. While most regions within condensed chromosomes are transcriptionally silent during mitosis, CEN are not Chan et al. In human cells, the cohesin-protecting protein Sgo1 Shugoshin is recruited to early mitotic kinetochores by the Bub1-phosphoryated centromeric histone H2A [phosphorylated at Thr; H2A TP ]. Schizosaccharomyces pombe CEN are transcribed during DNA replication, which may generate transcription—replication conflicts.
R-loops must be resolved; otherwise, they can provoke chromosome breaks and repeat-sequence recombinations. R-loops forming in centromeric chromatin or at pericentromeres or across the genome trigger Aurora B-mediated phosphorylation of local histone H3 at Ser10, as shown in yeast, C.
This mark stimulates confined chromatin condensation and restricts DNA replication and transcription Castellano-Pozo et al. No evidence exists for small CEN RNA processing products as documented for the transcripts derived from the pericentromeric chromatin see below. Genome-wide screens with Drosophila and human cells identified splicing factors that are required for cell division Goshima et al.
Also, purifications of the spliceosome from HeLa cell nuclear extracts revealed the presence of microtubule- and mitotic chromatin-interacting proteins Makarov et al.
Splicing factors also interact with MinSat transcripts in murine cells Maison et al. The co-transcriptional recruitment of the RNA processing machinery to nascent mitotic transcripts in Xenopus is an important step in kinetochore and spindle assembly. The transcripts are heterogeneous in length 40— nt but predominantly contain 40 and nt species Du et al. Although viable, they proliferated more slowly Kanellopoulou et al. No aberrant chromosome structures or aneuploidy was observed but the cells displayed differentiation defects.
Tight regulation and processing of these crasiRNAs seem integral to the epigenetic framework that is required for CEN establishment. Hammerhead ribozyme structures associated with transcribed satellite DNA sequences have been identified in salamanders Epstein and Gall, , schistostome flatworms Ferbeyre et al. All hammerhead ribozymes self-cleave multimeric satellite transcripts into monomer RNAs.
Centromere transcripts or small CEN RNA derivatives underlie the formation of ribonucleoprotein complexes that specify the CEN domains and establish correct kinetochore assembly and architecture. Treating mitotic human cells with alpha-amanitin lowered CENP-C levels at kinetochores and caused an increase in lagging chromosomes. Both proteins coincide at the CEN in metaphase and move to the contractile ring in cytokinesis. Knocking down alpha-satellite RNA in human cells Ideue et al.
Nonetheless, ectopic overexpression of satellite I RNA did not significantly affect chromosome segregation and CEN functions in human cells Ideue et al. RNA stimulates Aurora B kinase activity in vitro and in vivo , and a positive feedback loop exists between its kinase activity and its metaphase localization Wang et al.
Over RNAs were identified, of which were specific for mitosis, suggesting a cell cycle-regulated binding of target RNA. Identified RNAs encode proteins of the cytoskeleton, centrosome, transcription factors, and RNAs that are enriched on spindle microtubules Jambhekar et al. Centromeric chromatin in fission yeast and metazoans is flanked by constitutive heterochromatin.
The pericentromeric domains bind specific proteins and carry epigenetic marks that keep them in a transcriptionally inert state thereby insulating themselves from the enclosed CEN. It also actively recruits cohesin via the SUVH2 methyltransferase enzymes that trimethylate histone H4 at Lys20 to promote the bi-orientation of and tension development between the sister chromatids Bernard et al. Pericentromeres harbor promoter elements that recruit various transcription factors, including Ikaros in human cells Gurel et al.
The repeat sequences are not conserved between or within a species, suggesting that pericentromere transcription is epigenetically controlled. Indeed, it contains histone H3 variants H3. The pericentric histones are hypoacetylated, resulting in chromatin fiber compaction. Notwithstanding this repressive environment, pericentromeres are transcribed in many organisms.
A delicate balance between pericentromere and CEN transcription ensures chromosomal stability see next. SINE expression has been linked to establishing boundary elements and chromatin insulators across the genome Lunyak et al. Figure 4. RNA interference-based heterochromatin formation and maintenance at S. Upper panel: the S. Lowe panel: Regulation of the heterochromatic state of CEN sequences that flank the central core domain.
Adapted from Holoch and Moazed Transcription of pericentromeric chromatin occurs in many species and, except for the tRNA genes in fission yeast, is largely devoid of protein-encoding sequences Brown et al. Both otr elements are not required for CEN function during mitosis but provide a platform for the heterochromatin component of S.
The latter recruits chromodomain proteins Swi6 S. Deleting RNAi pathway genes dcr1 , ago1 or RdP1 caused chromosome missegregation due to defective silencing of the pericentromeric heterochromatin.
Pericentromere transcription and siRNA production in S. Hence, pericentromere silencing may be alleviated in S-phase as heterochromatin markers H3K9me and Swi6 become distributed on the replicated strands Chen et al. Without RNAi, homologous recombination repairs the stalled forks Zaratiegui et al. The importance of Dicer-dependent processing of pericentromere RNAs for heterochromatin assembly in vertebrates was demonstrated with chicken DT40 cells carrying a human chromosome Fukagawa et al. Eliminating Dicer provoked an accumulation of long pericentric alpha-satellite and SatIII transcripts, and caused mitotic defects due to precocious sister chromatid separation; attributed to HP1 loss and a misregulation of cohesin and SAC protein BubR1.
These findings indicated a role for Dicer in repressing pericentromere regions and other usually silent genetic elements Kanellopoulou et al. However, other than in chicken cells Fukagawa et al. Irrespective of how or if the RNAi pathway contributes, pericentromere transcripts in mammals seem involved in the formation and maintenance of heterochromatin. Depleting WDHD1 enhanced MajSat levels and reduced pericentromeric heterochromatin condensation, resulting in proliferation defects Hsieh et al.
However, a functional association with the RNAi machinery was not assessed Santenard et al. RNase treatment released HP1 and altered the spacing of the pericentromeric histones. HP1 preferentially binds to the forward strand of these RNAs, which remains bound to the site of transcription. Additional HP1 molecules then accumulate, connecting pericentromere transcription with heterochromatin formation Maison et al. In primary mouse embryonic fibroblasts, pericentromeric heterochromatin transcription is proliferation- and cell cycle-dependent Lu and Gilbert, Since the transcripts accumulate at the site of pericentromere replication, local transcription could promote heterochromatin reassembly at the replication fork.
Indeed, while HP1 is dispatched from heterochromatin during M-phase Muchardt et al. SUV39 is incorporated and stabilized in constitutive heterochromatin by chromatin-associated non-coding RNAs Johnson et al.
Heterochromatin activity in D. Involvement of siRNA pathways acting in heterochromatin formation in Drosophila has been hypothesized since a nuclear pool of transposable element-derived siRNAs 21 nt was shown to promote heterochromatin formation in somatic cells of Drosophila. Components of the RNAi pathway contributed to heterochromatin maintenance Fagegaltier et al.
As in S. RNAi activity seems to help establish heterochromatin in the early embryo, which can then be maintained in the absence of RNAi in somatic tissues Huisinga and Elgin, Contrary to D. Processing of satellite-derived transcripts by the RNAi pathway into siRNAs 21—24 nt has been reported for Arabidopsis , rice, and sugar beet May et al. The sequences of components of the RNAi pathway are present in the genome of T.
Satellite DNA has been associated with differentiation and development. Repetitive DNA is not transcribed in adult tissues presumably because it is hypermethylated Jeanpierre et al.
Antisense MajSat transcripts accumulate in the central nervous system of mouse embryos In adult mice, MajSat transcripts were identified only in highly proliferative tissues such as liver and testis Rudert et al. In chicken and zebrafish, alpha-satellite expression from the sense and antisense strands occurs in a regulated pattern during embryogenesis, possibly to control gene expression following transcript processing Li and Kirby, Before headfold formation in the chick and at 0—2 h post-fertilization hpf in zebrafish, blastodiscs expressed the alpha-repeat sequences.
By stage 9 and at 6—8 hpf, respectively, the expression localized to the head mesoderm, myocardium, pharyngeal endoderm, and cardiac neural crest. Because the expression occurred so early in zebrafish, the authors looked for the alpha-repeat transcripts within the maternal RNAs in single-cell and four-cell stage embryos. These stages occur within minutes of fertilization and before the start of zygotic transcription at 3 hpf.
High levels of the transcripts were found, supporting their maternal origin Li and Kirby, Pathological transcription of either region dramatically affects CEN insulation and activity, resulting in disturbed kinetochore formation and genetic instability. In human cells, the transcription of certain pericentromeric satellite sequences, in particular SatIII, is induced upon heat shock and exposure to heavy metals, chemicals, UV radiation, hyperosmotic, or oxidative conditions Figure 5A.
Importantly, while SatIII transcripts were up-regulated following heat shock, CEN transcripts were not, indicating that each domain is subject to different transcriptional control mechanisms Jolly et al. SatIII expression levels also depend on the type of stress that is experienced: MMS, etoposide, aphidicolin, and oxidative stress are weak inducers; UV and hyperosmosis have a moderate effect; and heat shock and cadmium are very strong activators.
In unstressed cells, SatIII sequences exist in a transcriptionally silent, closed heterochromatin conformation. RNAi knock-downs of these transcripts that range between 2 and 5 kb Jolly et al. Together, they correspond to mature nuclear stress bodies that accumulate at the pericentromeres Denegri et al. The number and size of the nuclear stress bodies correlate directly with SatIII expression Valgardsdottir et al.
Next, the granule clusters dissociate, the RNA-binding proteins redistribute through the nucleoplasm but the SatIII transcripts stay bound to the granules. At the same time, granules that are H3K9 methylated appear adjacent to the disassembling nuclear stress bodies. The transcripts are then cleaved, and a complex similar to the S.
Depending on the stress that is experienced, different transcription factors promote SatIII activation. Satellite transcript accumulation during heat stress also occurs in insects Pezer et al. In the beetle T. The production of these siRNAs is developmentally regulated but is strongly induced upon heat shock. During recovery, siRNA expression and histone modifications are restored to normal. Transient heterochromatin remodeling seems part of a stress-activated gene-expression program in beetles Pezer et al.
In Arabidopsis , a temperature upshift alleviated the silent state of CEN satellite sequences, pericentric 5S rDNA arrays, transposable elements, and B interspersed repeats.
Surprisingly, the pattern of repressive epigenetic marks within the heterochromatin was not affected, suggesting that the temperature-stimulated transcription activity bypassed these regulatory modifications Tittel-Elmer et al. Figure 5. A Regulation of pericentromere SatIII transcription in human cells following exposure to heat and other stresses. In the absence of stress, SatIII repeat sequences are epigenetically marked for silence H3K9me, pink dot and exist in a closed transcriptionally inert state blue nucleosomes.
Upon exposure to heat or other stresses, the monomeric HSF1 shown in green becomes upregulated, and forms homotrimers that after phosphorylation enter the nucleus. The granules disassemble and the RNA-binding proteins redistribute throughout the nucleoplasm.
SatIII transcripts may become processed into smaller fragments possibly by the RNAi machinery to protect and re-establish the heterochromatic state of the pericentromeric region comprising the SatIII repeats, possibly by recruiting epigenetic writing activity resulting in the establishment of the repressive H3K9me signals. B Transcriptional regulation of peri centric repeat sequences as identified in various tumors. The epigenetic marks and the enzymes responsible for introducing or removing them at histones or cytosine are indicated.
Blue nucleosomes: silent, purple nucleosomes: transcribed. The overproduction of peri centric transcripts can induce DNA damage, mitotic defects, genomic instability, and aneuploidy. Comparable ectopic overexpression of MinSat DNA led to decondensed CEN and mitotic defects such as multiple spindle attachments, loss of sister chromatid cohesion, aneuploidy, and cell death Bouzinba-Segard et al. X, the phosphorylated histone H2A. X variant that marks dsDNA breaks Zhu et al. These cells also exhibited bridged and lagging chromosomes as well as disorganized metaphase spindles Zhu et al.
X were also observed after nuclear injection of satellite RNA in human cells, indicating that high transcription intensity per se does not trigger the DNA damage response Zhu et al. The transcripts processed via an RNAi-dependent or -independent pathway could mediate heterochromatin reformation, as in S.
Analogous to X-chromosome inactivation by the long non-coding Xist RNA, the transcripts might recruit chromatin remodelers and DNA methyltransferases to establish a silent pericentric state.
Possibly, the transcripts could regulate local RNA splicing during the stress response by sequestering splicing factors. Via a position-effect mechanism, they might counteract the repressive nature of heterochromatin and activate nearby genes in cis or trans Eymery et al. Heterochromatin structure and expression change during aging. An up-regulation of MajSat expression in senescent cardiac muscle cells of aging mice but not in their brain or kidneys may be linked to mitochondria-induced oxidative stress Gaubatz and Cutler, Transcriptional activation of pericentromeres has been observed in replicative senescence and aging.
Upon extensive passaging of human fibroblasts, the cells entered replicative senescence, which correlated with an increased expression of pericentromere transcripts.
The pericentromeric heterochromatin was decondensed and exhibited reduced DNA methylation. Here, the produced transcripts may not have a specific biological role but rather be the consequence of a senescent state of the heterochromatin itself Enukashvily et al. The latter arises from mutations in the laminA gene, which encodes a component of the nuclear lamina that maintains the structural integrity of the nucleus.
Lamins are crucial for pericentromeric heterochromatin organization in interphase cells Solovei et al. Pericentromeric heterochromatin was show to lose H3K9me3 and HP1 proteins in older flies and human cells, leading to an anomalous expression of satellite sequences Scaffidi and Misteli, ; Shumaker et al.
Loss of pericentric silencing may drive age-related genome instability and death since the cells from older individuals or progeria patients are characterized by a global loss of heterochromatin marks, and increase in DNA damage Scaffidi and Misteli, ; Shumaker et al.
The transcriptional misregulation of the SatII and SatIII pericentromeric satellite sequences, and altered epigenetic state of pericentromeric chromatin characterizes many cancers and genetic disorders Shumaker et al. In contrast, in healthy reference tissues, only 0. The transcripts were highly heterogeneous —8, nt and transcribed only from the forward strand. To determine what could be promoting SatII hyperexpression, linear regression analysis was performed to identify transcripts that were co-regulated with the mouse MajSat or human alpha-satellite sequences.
Several genes involved in neuronal cell fate and stem cell pathways, that contained LINE1 transposable elements were highly expressed Ting et al. A LINE1 insertion upstream of their transcription start sites can underlie their misregulation, contributing to cellular transformation. Whole-genome sequencing showed that SatII copy number gain commonly characterizes human colon tumors, and is linked with low survival Bersani et al.
Healthy human testis tissue showed a high expression of pericentromeres, while in cancers their expression was silent Eymery et al. Impairment of this interaction causes an overproduction of CEN and pericentromere transcripts Gopalakrishnan et al. The tumor-suppressing, heterochromatin-associating lysine demethylase 2A KDM2A is downregulated in prostate cancer Frescas et al. Via its Jumonji domain, the enzyme demethylates the pericentromeric H3K36me2 modification to silence the heterochromatin.
KDM2A depletion resulted in a loss of HP1 and elevated alpha-satellite and MajSat transcription in human and mouse cells, respectively. Phenotypes included genomic instability, sister chromatid misalignment, chromosome breaks, and anaphase bridges. The lower the level of KDM2A expression, the more severe the tumor grade in prostate cancer, linking hypermethylation and increased peri centromere transcription with cancer growth Frescas et al. While the levels of CEN and pericentromere transcripts in these tumors were not quantitated, their production was likely derepressed.
A forced accumulation of MinSat transcripts, in sense orientation, provoked a mislocalization of kinetochore proteins, affected chromosome segregation, sister chromatid cohesion, and induced modifications of CEN epigenetic hallmarks.
Possibly, anomalous levels of CEN transcripts interfere with kinetochore and cohesin recruitment Bouzinba-Segard et al. Of note, ectopic overexpression of alpha-satellite DNA in human cells led to chromosome loss but not to reduced methylation of the DNA. In contrast, DNA demethylation caused pathological alpha-satellite transcription and chromosome loss in human cells Ichida et al.
Its inactivation led to H3K18 hyperacetylation likely by the histone acetyltransferase GCN5, reversal of heterochromatin silencing, mitotic defects, genomic instability, and senescence. Importantly, depletion of the transcripts through RNAi rescued the phenotypes Tasselli et al.
Mutations in the hereditary ovarian and breast cancer susceptibility gene BRCA1, which acts as a tumor suppressor, led to genomic instability. While BRCA1 acts in DNA replication and damage repair, control of the cell cycle, and many other regulatory functions, the protein was recently shown to also determine the epigenetic states of centromeric and pericentric chromatin Zhu et al.
While the latter may have produced defective heterochromatin as indicated by reduced HP1 levels , it is unclear which factors promoted alpha-satellite transcription in the BRCA1-deficient cells. Ectopically expressing H2A fused to ubiquitin reversed the above BRCA1-loss phenotypes, whereas the ectopic expression of satellite DNA phenocopied it, resulting in DNA damage and genomic instability, cell cycle checkpoint defects, and centrosome amplification, indicating that overexpressed peri centromere transcripts could contribute to malignancy Zhu et al.
The tumor-suppressing transcription factor Prep1 is associated with DNA damage control and the management of histone methylation levels Iotti et al. Indeed, upon downregulating Prep1 in mouse or human cells, DNA damage increased. This phenotype, which is generated through an unknown mechanism, caused a widespread increase in the repressive histone mark H3K9me3. Intriguingly, the decrease in CEN and pericentromere transcript production led to the same phenotypes as in cells overexpressing them, including aneuploidy, miniature chromosomes, Robertsonian translocations, and CEN duplications Iotti et al.
Tumor-suppressing transcription factor p53 cooperates with DNA methylation activity to silence a large part of the mouse genome. Accumulation of these transcripts, which are capable of forming dsRNAs, was complemented by a potent apoptosis-inducing type I interferon response. The authors suggested a model in which the downregulation of these repeat sequences is controlled by pdriven transcriptional silencing, DNA methylation-based suppression of transcription, and the suicidal type I interferon response, which eliminates the cells that escaped the first two lines of control Leonova et al.
Peri centromere silencing is also regulated by the Polycomb repressive complexes PRC1 and PRC2, which are commonly misregulated in cancer Blackledge et al.
In Rb1 mutant mice, which are defective in recruiting EZH2 to repetitive sequences, a transcriptional derepression of satellite DNA was observed, which induced susceptibility to lymphoma Ishak et al. SatII overexpression characterizes myriad cancerous and precancerous lesions, suggesting that SatII RNA levels might be a good predictor or indicator of cancer Ting et al.
Indeed, RNA in situ hybridization analysis of SatII expression in biopsies proved a better diagnostic for pancreatic cancer than standard histopathological analysis Ting et al. A convenient and highly sensitive method for quantitating circulating satellite repeat RNAs in blood serum Kishikawa et al.
Patients with pancreatic ductal carcinoma PDAC were efficiently discriminated from healthy individuals, while patients with intraductal papillary mucinous neoplasm, a precancerous lesion of PDAC, could also be accurately identified. This simple and cheap test allows for early prognosis, quick screens, and regular follow-ups of PDAC progression. This method may well be adapted to quantitate additional peri centromere transcripts in other cancers as well. Kinetochore subunit overexpression Thiru et al.
Similarly, CEN and pericentromere transcript levels in conjunction with the peri centromeric methylation, acetylation, or ubiquitination state may serve as valuable readouts of cancer grade and survival. They may also represent novel therapeutic targets. Nucleic acid therapeutics aimed at peri centromere repeats may provide alternative objectives for the future.
They are transcribed in a cell- or tissue-specific manner, making them exceptional objectives. Clinical trials are already underway to similarly target highly structured bacterial or viral riboswitches using small-molecule inhibitors to treat bacterial and viral infections, respectively Howe et al. Small-molecule ligands targeting structural elements in these CEN or pericentromere RNAs could potentially destabilize the transcript or interfere allosterically with CEN-protein binding to confer a therapeutic effect, although this remains purely hypothetical.
With recent advances in genome editing methods, it is possible to achieve transcriptional silencing of peri centromere repeats via CRISPR interference Gilbert et al. These experiments suggest that downregulating pathologically expressed peri centromeric elements could well be feasible Zhang et al. However, only the future will tell to which extent these approaches will translate into clinical scenarios.
The continuous identification and functional characterization of new epigenetic activities enzymes, histone modifications that impinge on centromeric and pericentromere domains via ever more sensitive mass spectrometry approaches will take our understanding of CEN, kinetochore, and pericentromere biology to the next level.
In addition, transcription factors that drive peri centromere transcription in healthy and diseased cells must be identified as their biology and influences on the spatiotemporal regulation of the CEN and pericentric regions remains largely unknown.
The same is true for regulators that act upon the RNAPII complex to orchestrate its activity recruitment, elongation, termination at peri centromeres.
Kinases and phosphatase may be prime candidates. A better understanding of RNAi pathway involvement in mammalian biology would be welcomed as well. KS and PDW wrote the paper and made the figures.
Both authors have approved of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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