Partitioning of cancer therapeutics in nuclear condensates
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ABSTRACT:
PROVIDER: PRJNA627353 | ENA |
REPOSITORIES: ENA
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Project description:The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here we consider whether condensates concentrate small molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to impact the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.
2020-04-27 | GSE149085 | GEO
Project description: Not available
| S-EPMC7735713 | biostudies-literature
Project description:The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. These chromatin compartments include enhancer-associated clusters whose dynamic establishment and functioning depends on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However how chromatin modifiers contribute to the assembly of enhancer-associated condensates have not been addressed. We herein defined the non-catalytic function of MLL4 in driving the formation active nuclear condensates and its interplay with Polycomb compartment in determining the nuclear architecture. By interrogating the role of haploinsufficiency of KMT2D in Kabuki Syndrome, we found that MLL4 guides the assembly of enhancer-associated condensates through liquid-liquid phase separation. The loss-of-function of MLL4 impaired the correct chromatin compartmentalization of Polycomb proteins, altering nuclear architecture. By releasing the nuclear mechanical stress through the inhibition of the mechano-sensor ATR, we re-established the mechano-signaling of MSCs and their commitments towards chondrocytes. This study supports the notion that MLL4 contributes to the functional partitioning of chromatin, which is required to determine the structure and the mechanical properties of the nucleus.
2020-09-09 | GSE135550 | GEO
Project description:The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depends on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However how chromatin players contribute to the assembly of transcriptional condensates has not been addressed. By interrogating the effect of KMT2D haploinsufficiency in Kabuki Syndrome, we found that MLL4 contributes in the assembly of transcriptional condensates through liquid-liquid phase separation. MLL4 loss-of-function impaired Polycomb-dependent chromatin compartmentalization, altering nuclear architecture. By releasing the nuclear mechanical stress through the inhibition of the mechano-sensor ATR, we re-established the mechano-signaling of mesenchymal stem cells and their commitment towards chondrocytes both in vitro and in vivo. This study supports the notion that in Kabuki Syndrome the haploinsufficiency of MLL4 causes an altered functional partitioning of chromatin, which determines the architecture and mechanical properties of the nucleus.
2020-09-22 | PXD021616 | Pride
Project description:Transcription factors are among the most attractive therapeutic targets but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors’ activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in mouse models of prostate cancer and castration resistant prostate cancer. These results establish a generalizable framework to target the phase-separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent.
2023-07-31 | GSE232849 | GEO
Project description:Epigenetic and metabolic reprogrammings are implicated in cancer progression with unclear mechanisms. We report here that the histone methyltransferase NSD2 drives cancer cell and tumor resistance to therapeutics such as tamoxifen, doxorubicin, and radiation by reprogramming of glucose metabolism. NSD2 coordinately up-regulates expression of TIGAR, HK2 and G6PD and stimulates pentose phosphate pathway (PPP) production of NADPH for ROS reduction. We discover that elevated expression of TIGAR, previously characterized as a fructose-2,6-bisphosphatase, is localized in the nuclei of resistant tumor cells where it stimulates NSD2 expression and global H3K36me2 mark. Mechanistically, TIGAR interacts with the antioxidant regulator Nrf2 and facilitates chromatin assembly of Nrf2-H3K4me3 methylase MLL1 and elongating Pol-II, independent of its metabolic enzymatic activity. In human tumors, high levels of NSD2 correlate strongly with early recurrence and poor survival and are associated with nuclear-localized TIGAR. This study defines a nuclear TIGAR-mediated, epigenetic autoregulatory loop functioning in redox rebalance for resistance to tumor therapeutics. A total of 4 samples were analyzed in this study. The study included two cell lines, MCF7 and the tamoxifen-resistant subline TMR. Both were were cultured in medium containing vehicle control and/or 4-hydroxytamoxifen (Tam). The untreated MCF7 and TMR cell lines served as controls for the study.
2016-10-22 | E-GEOD-62613 | biostudies-arrayexpress
Project description:Chromatin is partitioned into distinct topological domains in an activity-dependent manner, with topological boundaries limiting the interaction between adjacent domains. Recent studies support the concept that several well-established nuclear compartments are assembled as ribonucleoprotein condensates. Here we ask whether the physical processes driving the assembly of the nuclear condensates play any role in three-dimensional chromatin architecture. We report that the insulation of approximately 20% of topological boundaries in human embryonic stem cells is substantially weakened following brief treatment with 1,6-hexanediol, a chemical known to disrupt several nuclear condensates. The disrupted boundaries are characterized by a high level of transcription, striking spatial clustering, and the augmented presence of transcription units widely expressed in diverse cell types. These topological boundary regions tend to be spatially associated, even inter-chromosomally, and segregate with nuclear speckles. These observations reveal a previously unappreciated mode of genome organization mediated by conserved boundary elements harboring widely-expressed transcription units and associated transcriptional condensates.
2022-06-15 | GSE195561 | GEO
Project description:Chromatin is partitioned into distinct topological domains in an activity-dependent manner, with topological boundaries limiting the interaction between adjacent domains. Recent studies support the concept that several well-established nuclear compartments are assembled as ribonucleoprotein condensates. Here we ask whether the physical processes driving the assembly of the nuclear condensates play any role in three-dimensional chromatin architecture. We report that the insulation of approximately 20% of topological boundaries in human embryonic stem cells is substantially weakened following brief treatment with 1,6-hexanediol, a chemical known to disrupt several nuclear condensates. The disrupted boundaries are characterized by a high level of transcription, striking spatial clustering, and the augmented presence of transcription units widely expressed in diverse cell types. These topological boundary regions tend to be spatially associated, even inter-chromosomally, and segregate with nuclear speckles. These observations reveal a previously unappreciated mode of genome organization mediated by conserved boundary elements harboring widely-expressed transcription units and associated transcriptional condensates.
2022-06-15 | GSE195565 | GEO
Project description:Chromatin is partitioned into distinct topological domains in an activity-dependent manner, with topological boundaries limiting the interaction between adjacent domains. Recent studies support the concept that several well-established nuclear compartments are assembled as ribonucleoprotein condensates. Here we ask whether the physical processes driving the assembly of the nuclear condensates play any role in three-dimensional chromatin architecture. We report that the insulation of approximately 20% of topological boundaries in human embryonic stem cells is substantially weakened following brief treatment with 1,6-hexanediol, a chemical known to disrupt several nuclear condensates. The disrupted boundaries are characterized by a high level of transcription, striking spatial clustering, and the augmented presence of transcription units widely expressed in diverse cell types. These topological boundary regions tend to be spatially associated, even inter-chromosomally, and segregate with nuclear speckles. These observations reveal a previously unappreciated mode of genome organization mediated by conserved boundary elements harboring widely-expressed transcription units and associated transcriptional condensates.
2022-06-15 | GSE195563 | GEO
Project description:Chromatin is partitioned into distinct topological domains in an activity-dependent manner, with topological boundaries limiting the interaction between adjacent domains. Recent studies support the concept that several well-established nuclear compartments are assembled as ribonucleoprotein condensates. Here we ask whether the physical processes driving the assembly of the nuclear condensates play any role in three-dimensional chromatin architecture. We report that the insulation of approximately 20% of topological boundaries in human embryonic stem cells is substantially weakened following brief treatment with 1,6-hexanediol, a chemical known to disrupt several nuclear condensates. The disrupted boundaries are characterized by a high level of transcription, striking spatial clustering, and the augmented presence of transcription units widely expressed in diverse cell types. These topological boundary regions tend to be spatially associated, even inter-chromosomally, and segregate with nuclear speckles. These observations reveal a previously unappreciated mode of genome organization mediated by conserved boundary elements harboring widely-expressed transcription units and associated transcriptional condensates.
2022-06-15 | GSE195562 | GEO