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Partitioning of cancer therapeutics in nuclear condensates

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149085 | GEO | 2020/04/27

REPOSITORIES: GEO

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MeCP2 links heterochromatin condensates and neurodevelopmental disease

Project description:MeCP2 (methyl CpG binding protein 2) is a key component of constitutive heterochromatin, which plays important roles in chromosome maintenance and transcriptional silencing. Mutations in MeCP2 cause Rett syndrome (RTT), a postnatal progressive neurodevelopmental disorder associated with severe mental disability and autism-like symptoms that manifests in girls during early childhood. Heterochromatin, long considered a dense and relatively static structure, is now understood to exhibit properties consistent with a liquid-like condensate. Here we report that MeCP2 is a dynamic component of heterochromatin condensates in cells, is stimulated by DNA to form liquid-like condensates, contains multiple domains that contribute to condensate formation, manifests physicochemical properties that selectively concentrate heterochromatin cofactors compared to components of transcriptionally active condensates, and when altered by RTT-causing mutations is disrupted in its ability to form condensates. We propose that MeCP2 enhances heterochromatin/euchromatin separation through its condensate partitioning properties and that condensate disruption may be a common consequence of RTT patient mutations.

2020-06-23 | GSE139033 | GEO

Partitioning of cancer therapeutics in nuclear condensates

Project description:Partitioning of cancer therapeutics in nuclear condensates

| PRJNA627353 | ENA

ATAC-seq profiling of open chromatin in PLC-PRF cells

Project description:Epithelial–mesenchymal transition (EMT) is an important mechanism of metastasis and malignant progression of hepatocellular carcinoma (HCC). However, the transcriptional regulation mechanism of EMT remains poorly understood. Some transcriptional co-activators can form phase-separated condensates at super-enhancers that compartmentalize and concentrate the transcription apparatus to drive robust gene expression. Here, we demonstrate that Twist1 and YY1, interact with p300 and form phase-separated local high-concentration interaction hubs at super-enhancers of miRNA-9 and activate its expression to induce EMT and promote the malignant evolution of HCC. Phase separation disrupted by metformin perturbs Twist–YY1 condensates, thereby inhibiting EMT. To explore how the Twist1 complex regulates miR-9 expression by binding SE region, we performed Twist1 ChIP-seq combined with H3K4me3, H3K4me1, H3K27ac, DNAse, p300, and YY1 ChIP-seq data to detect the SEs of miR-9. After metformin treatment, the peak of Twist1/YY1 on miR-9 SE decreased. Metformin specifically affects the binding of Twist1/YY1 to the miR-9 SE region. 1,6-hexanediol, as an aliphatic alcohol, can weaken hydrophobic interactions and inhibit liquid–liquid phase separation by disrupting hydrophobic interactions. In order to prove Twist1/YY1 interaction at these sites requires phase separation, we detect the accessibility of miR-9 SE regions in 1,6-hexanediol-treated cells. The result showed a general decrease in the accessibility of miR-9 super-enhancer regions in 1,6-hexanediol-treated cells and Twist1 / YY1 combines the SE region of miR-9 in the form of phase separation.

2019-12-13 | GSE141964 | GEO

ChipSeq of Twist1 and YY1 in PLC-PRF-5 cells

2019-12-13 | GSE141965 | GEO

High-precision mapping of nuclear pore-chromatin interactions reveals new principles of genome organization at the nuclear envelope

Project description:The role of nuclear pore complexes (NPCs) in genome organization remains poorly characterized due to technical limitations in probing genome-wide protein-DNA interactions that are specific to the nuclear envelope. Here, we developed a sensitive method, NPC-DamID, which combines in vitro reconstitution of nuclear import and DamID technology. This fixation-free method specifically identifies genomic DNA interactions at the NPCs in intact nuclei. We found that NPCs are preferentially associated with common and hierarchically arranged super-enhancers (SEs) across multiple cells and tissue types. We also uncovered phase-separated condensates at NPCs that compartmentalize and concentrate transcriptional coactivators and structural proteins at SE-regulated genes. Our results support the idea that NPCs are sites of anchoring SE regulatory hubs through their interaction with CTCF and also maintains the conformation of SEs through interaction with structural proteins of SEs like Med1 and PolII.

2021-08-02 | GSE176106 | GEO

Circadian clock regulation by compartmentalized protein translation

Project description:Cells exquisitely compartmentalize many biochemical reactions through phase-separated membrane-less organelles. Besides spatial organization, many biological processes are temporally regulated. While both transcription and translation oscillate in a rhythmic manner, the regulatory mechanism of the latter is understudied. Here we report that the translational regulation during circadian cycles is associated with oscillating phase separation controlled by Ataxin-2 and Ataxin-2L. Ataxin-2/2L forms rhythmic condensates through phase separation in the mammalian central clock suprachiasmatic nucleus to selectively concentrate the transcripts of the core clock genes and recruit the mRNA translation machinery. The rhythmic translational activation is abolished in cells and mouse circadian behavior is altered in the absence of Ataxin-2/2L. During aging or neurodegeneration, Ataxin-2/2L form large, irreversible puncta that no longer regulate translation. Overall, our results unveil Ataxin-2/2L’s role as the master regulators of rhythmic translation via a oscillating phase-separation, and explained the reason for their dysfunction in disease states.

2023-06-24 | GSE222433 | GEO

MLL4 establishes enhancer-associated condensates to counterbalance Polycomb-mediated nuclear mechanical stress in Kabuki Syndrome [3'UTR RNA-seq]

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

An RNA-based precision oncology platform for patient-therapy alignment in a diverse set of treatment resistant malignancies

Project description:We use a Master Regular-based precision cancer medicine framework to predict drug sensitivity. The network based analysis uses RNASeq profiles of patient tumors, in conjunction with de novo drug mechanism analysis from high throughput drug screens with post-perturbation RNASeq profiles performed in cognate cell line models. The analysis aims to predict available antineoplastic drugs most likely to invert the aberrant protein activity state of individual tumors. Validation of predictions was performed in corresponding patient-derived xenograft (PDX) mice. Pharmacodynamic samples were obtained from PDX mice after the third dose for RNASeq and downstream analysis.

2022-09-10 | GSE212854 | GEO

Project description:soil microorganisms and soil physicochemical properties

| PRJNA636942 | ENA

Chemical-Induced Phase Transition and Global Conformational Reorganization of Chromatin [RNA-seq]

Project description:Chemicals or drugs were demonstrated to accumulate within biomolecule condensates formed through phase separation in cells. Here, we employed super-resolution imaging to search for chemicals that induce phase transition of chromatin at the microscale. We found that adriamycin (doxorubicin), a widely-used chemotherapeutic drug against malignancies, is able to induce local condensation and global conformational change of chromatin in cancer and primary cells. Hi-C and ATAC-seq experiments demonstrated that adriamycin-induced chromatin condensation is accompanied by weakened chromatin interaction within topologically-associated domains, compartment A/B switching, lower chromatin accessibility, and corresponding transcriptomic changes. Mechanistically, adriamycin complexes with histone H1 and induces the phase transition of H1, forming fibrous aggregates in vitro. Our results reveal a new action mechanism of an anti-cancer drug discovered for decades, demonstrate the link between the physical properties of chromatin and gene expression, and suggest that interactions between drugs and biomolecules could exert profound effects on cells.

2023-01-11 | GSE222221 | GEO

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