Similar Datasets
Project description:The evolution of migratory populations of cells within solid tumours represents a critical stage during cancer metastasis. We have previously reported the enhanced migratory properties of one such population, marked by the expression of CD66, within cervical cancers. However, it is not clear what mechanisms drive such migratory populations, and how these cells would retain a “memory” of initial migration-inducing cues during metastasis. Here, we describe the role of a Suv39H1-low heterochromatin state as a driver of cervical cancer migratory populations. Cervical cancer cells were sorted based on migratory ability in vitro. These migrated populations show low Suv39H1, and Suv39H1 knockdown enhances cell migration. Using histopathology to examine clinical carcinoma progression, initial progression showed expansion of a proliferative Suv39H1high population, followed by the emergence of a sarcomatoid, migratory Suv39H1low cell population in advanced stages. Additionally, meta-analysis of TCGA data revealed that low tumoural Suv39H1 also correlated with lower patient survival, and with expression signatures of migration, TGF-β signalling, and links with a CD66 cell signature. Lastly, using RNA-Seq and H3K9me3 ChIP-Seq on migrated populations in vitro, it was observed that these populations show Suv39H1-linked transcriptome alterations and broad scale H3K9me3 remodelling. This Suv39H1-linked heterochromatin regulation could explain plasticity in migratory and metastatic populations, and allows for a “memory” of migration inducing cues, through metastable changes in chromatin conformation. The understanding of such regulatory mechanisms in migratory populations may prove valuable in efforts to develop anti-metastatic strategies.
2019-03-01 | GSE103793 | GEO
Project description:The evolution of migratory populations of cells within solid tumours represents a critical stage during cancer metastasis. We have previously reported the enhanced migratory properties of one such population, marked by the expression of CD66, within cervical cancers. However, it is not clear what mechanisms drive such migratory populations, and how these cells would retain a “memory” of initial migration-inducing cues during metastasis. Here, we describe the role of a Suv39H1-low heterochromatin state as a driver of cervical cancer migratory populations. Cervical cancer cells were sorted based on migratory ability in vitro. These migrated populations show low Suv39H1, and Suv39H1 knockdown enhances cell migration. Using histopathology to examine clinical carcinoma progression, initial progression showed expansion of a proliferative Suv39H1high population, followed by the emergence of a sarcomatoid, migratory Suv39H1low cell population in advanced stages. Additionally, meta-analysis of TCGA data revealed that low tumoural Suv39H1 also correlated with lower patient survival, and with expression signatures of migration, TGF-β signalling, and links with a CD66 cell signature. Lastly, using RNA-Seq and H3K9me3 ChIP-Seq on migrated populations in vitro, it was observed that these populations show Suv39H1-linked transcriptome alterations and broad scale H3K9me3 remodelling. This Suv39H1-linked heterochromatin regulation could explain plasticity in migratory and metastatic populations, and allows for a “memory” of migration inducing cues, through metastable changes in chromatin conformation. The understanding of such regulatory mechanisms in migratory populations may prove valuable in efforts to develop anti-metastatic strategies.
2019-03-01 | GSE103792 | GEO
Project description:A Suv39H1-low chromatin state drives migratory cell populations in cervical cancer
| PRJNA407059 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2012-02-20 | GSE30760 | GEO
Project description:Specialized chromatin domains contribute to nuclear organization and regulation of gene expression. Gene-poor regions are di- and trimethylated at lysine 9 of histone H3 (H3K9me2 and H3K9me3) by the histone methyltransferase Suv39h1. This enzyme harnesses a positive feedback loop to spread H3K9me2 and H3K9me3 over extended heterochromatic regions. However, little is known about how feedback loops operate on complex biopolymers such as chromatin, in part because of the difficulty in obtaining suitable substrates. Here we describe the synthesis of multidomain 'designer chromatin' templates and their application to dissecting the regulation of human Suv39h1. We uncovered a two-step activation switch where H3K9me3 recognition and subsequent anchoring of the enzyme to chromatin allosterically promotes methylation activity and confirmed that this mechanism contributes to chromatin recognition in cells. We propose that this mechanism serves as a paradigm in chromatin biochemistry, as it enables highly dynamic sampling of chromatin state combined with targeted modification of desired genomic regions.
| S-EPMC4876634 | biostudies-literature
Project description:The development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human haematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains the nucleoporin IDR-tandemly dispersed repeats of phenylalanine and glycine residues1,2. However, how unstructured IDRs contribute to oncogenesis remains unclear. Here we show that IDRs contained within NUP98-HOXA9, a homeodomain-containing transcription factor chimera recurrently detected in leukaemias1,2, are essential for establishing liquid-liquid phase separation (LLPS) puncta of chimera and for inducing leukaemic transformation. Notably, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera transcription factors, but also is required for the formation of a broad 'super-enhancer'-like binding pattern typically seen at leukaemogenic genes, which potentiates transcriptional activation. An artificial HOX chimera, created by replacing the phenylalanine and glycine repeats of NUP98 with an unrelated LLPS-forming IDR of the FUS protein3,4, had similar enhancing effects on the genome-wide binding and target gene activation of the chimera. Deeply sequenced Hi-C revealed that phase-separated NUP98-HOXA9 induces CTCF-independent chromatin loops that are enriched at proto-oncogenes. Together, this report describes a proof-of-principle example in which cancer acquires mutation to establish oncogenic transcription factor condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumourous transformation. As LLPS-competent molecules are frequently implicated in diseases1,2,4-7, this mechanism can potentially be generalized to many malignant and pathological settings.
| S-EPMC8647409 | biostudies-literature
Project description:The expression, biological functions and underlying molecular mechanisms of endothelial cell-specific molecule 1 (ESM1) in human cervical cancer remain unclear. Bioinformatics analysis revealed that ESM1 expression was significantly elevated in human cervical cancer tissues, correlating with patients' poor prognosis. Moreover, ESM1 mRNA and protein upregulation was detected in local cervical cancer tissues and various cervical cancer cells. In established and primary cervical cancer cells, ESM1 shRNA or CRISPR/Cas9-induced ESM1 KO hindered cell proliferation, cell cycle progression, in vitro cell migration and invasion, and induced significant apoptosis. Whereas ESM1 overexpression by a lentiviral construct accelerated proliferation and migration of cervical cancer cells. Further bioinformatics studies and RNA sequencing data discovered that ESM1-assocaited differentially expressed genes (DEGs) were enriched in PI3K-Akt and epithelial-mesenchymal transition (EMT) cascades. Indeed, PI3K-Akt cascade and expression of EMT-promoting proteins were decreased after ESM1 silencing in cervical cancer cells, but increased following ESM1 overexpression. Further studies demonstrated that SYT13 (synaptotagmin 13) could be a primary target gene of ESM1. SYT13 silencing potently inhibited ESM1-overexpression-induced PI3K-Akt cascade activation and cervical cancer cell migration/invasion. In vivo, ESM1 knockout hindered SiHa cervical cancer xenograft growth in mice. In ESM1-knockout xenografts tissues, PI3K-Akt inhibition, EMT-promoting proteins downregulation and apoptosis activation were detected. In conclusion, overexpressed ESM1 is important for cervical cancer growth in vitro and in vivo, possibly by promoting PI3K-Akt activation and EMT progression. ESM1 represents as a promising diagnostic marker and potential therapeutic target of cervical cancer.
| S-EPMC9755307 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-08-08 | E-GEOD-60103 | biostudies-arrayexpress
Project description:Centromere chromatin containing histone H3 variant CENP-A is required for accurate chromosome segregation as a foundation for kinetochore assembly. Human centromere chromatin assembles on a part of the long ?-satellite (alphoid) DNA array, where it is flanked by pericentric heterochromatin. Heterochromatin spreads into adjacent chromatin and represses gene expression, and it can antagonize centromere function or CENP-A assembly. Here, we demonstrate an interaction between CENP-A assembly factor M18BP1 and acetyltransferase KAT7/HBO1/MYST2. Knocking out KAT7 in HeLa cells reduced centromeric CENP-A assembly. Mitotic chromosome misalignment and micronuclei formation increased in the knockout cells and were enhanced when the histone H3-K9 trimethylase Suv39h1 was overproduced. Tethering KAT7 to an ectopic alphoid DNA integration site removed heterochromatic H3K9me3 modification and was sufficient to stimulate new CENP-A or histone H3.3 assembly. Thus, KAT7-containing acetyltransferases associating with the Mis18 complex provides competence for histone turnover/exchange activity on alphoid DNA and prevents Suv39h1-mediated heterochromatin invasion into centromeres.
| S-EPMC4906249 | biostudies-other
Project description:The hippocampus, including the dorsal dentate gyrus (dDG), and cortex engage in bidirectional communication. We propose that low-frequency activity in hippocampal-cortical pathways contributes to brain-wide resting-state connectivity to integrate sensory information. Using optogenetic stimulation and brain-wide fMRI and resting-state fMRI (rsfMRI), we determined the large-scale effects of spatiotemporal-specific downstream propagation of hippocampal activity. Low-frequency (1 Hz), but not high-frequency (40 Hz), stimulation of dDG excitatory neurons evoked robust cortical and subcortical brain-wide fMRI responses. More importantly, it enhanced interhemispheric rsfMRI connectivity in various cortices and hippocampus. Subsequent local field potential recordings revealed an increase in slow oscillations in dorsal hippocampus and visual cortex, interhemispheric visual cortical connectivity, and hippocampal-cortical connectivity. Meanwhile, pharmacological inactivation of dDG neurons decreased interhemispheric rsfMRI connectivity. Functionally, visually evoked fMRI responses in visual regions also increased during and after low-frequency dDG stimulation. Together, our results indicate that low-frequency activity robustly propagates in the dorsal hippocampal-cortical pathway, drives interhemispheric cortical rsfMRI connectivity, and mediates visual processing.
| S-EPMC5565425 | biostudies-other