Stress-induced nuclear condensation of NELF drives global transcriptional downregulation
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ABSTRACT:
PROVIDER: PRJNA588093 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10409000.fastq.gz | Fastqsanger.gz | |||
| SRR10409001.fastq.gz | Fastqsanger.gz | |||
| SRR10409002.fastq.gz | Fastqsanger.gz | |||
| SRR10409003.fastq.gz | Fastqsanger.gz | |||
| SRR10409004.fastq.gz | Fastqsanger.gz |
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Project description:In response to stress, human cells actively downregulate ongoing gene expression programs. Translational downregulation is accompanied by the assembly of stress granules which are cytosolic condensates containing ribosomes and mRNA. Transcriptional downregulation is caused by an increased recruitment of Negative Elongation Factors (NELF) to promoters, inhibiting RNA Pol II elongation. We report here that NELF forms nuclear condensates upon stress which can be recapitulated by liquid-liquid phase separation of recombinant NELF in vitro. Stress leads to rapid dephosphorylation and SUMOylation of NELF in cells facilitating condensate formation driven by intrinsically disordered domains of NELFA and NELFE subunits. Using NELF mutants that do not form condensates we provide evidence that condensation is required for increased recruitment of NELF to downregulated promoters and cellular survival in stress. Thus, our study has uncovered a novel nuclear condensate that is conceptually similar to cytosolic stress granule in downregulating gene expression during stressful conditions.
2021-02-05 | GSE140053 | GEO
Project description:In response to stress, human cells coordinately downregulate transcription and translation of housekeeping genes. To downregulate transcription, the negative elongation factor (NELF) is recruited to gene promoters impairing RNA polymerase II elongation. Here we report that NELF rapidly forms nuclear condensates upon stress in human cells. Condensate formation requires NELF dephosphorylation and SUMOylation induced by stress. The intrinsically disordered region (IDR) in NELFA is necessary for nuclear NELF condensation and can be functionally replaced by the IDR of FUS or EWSR1 protein. We find that biomolecular condensation facilitates enhanced recruitment of NELF to promoters upon stress to drive transcriptional downregulation. Importantly, NELF condensation is required for cellular viability under stressful conditions. We propose that stress-induced NELF condensates reported here are nuclear counterparts of cytosolic stress granules. These two stress-inducible condensates may drive the coordinated downregulation of transcription and translation, likely forming a critical node of the stress survival strategy.
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Project description:Downregulation of SENP1 impairs nuclear condensation of MEF2C and deteriorates ischemic cardiomyopathy
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Project description:Nuclear Condensation of NUP98-Fusion Proteins drives leukemogenic gene expression
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Project description:NUP98-fusion proteins cause leukemia via unknown molecular mechanisms. All NUP98-fusion proteins share an intrinsically disordered region (IDR) featuring >35 repeats of Phenylalanine-Glycine (FG) in the NUP98 N-terminus. Conversely, C-terminal NUP98-fusion partners often have critical functions in gene control. Given these structural features we hypothesized that mechanisms of oncogenic transformation by NUP98-fusion proteins are hard-wired in their protein interactomes. Affinity purification coupled to mass spectrometry and confocal imaging of five distinct NUP98-fusion proteins revealed that conserved interactors were enriched for proteins involved in biomolecular condensation and that they co-localized with NUP98-fusion proteins in nuclear puncta. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. An artificial FG-repeat-containing fusion protein phenocopied the nuclear localization patterns of NUP98-fusion proteins and their capability to drive oncogenic gene expression programs. Thus, we propose that IDR-containing fusion proteins uniquely combine biomolecular condensation with transcriptional control to induce cancer.
2020-12-23 | PXD022518 | Pride
Project description:Mammalian terminal erythropoiesis involves chromatin and nuclear condensation followed by enucleation. Late-stage erythroblasts undergo caspase-mediated nuclear opening formation that is important for nuclear condensation through partial release of histones. It remains unknown whether nuclear opening and histone release influence the three-dimensional (3D) genomic organization during terminal erythropoiesis. Here, we compared the genome wide 3D organization, chromatin accessibility, and transcriptome of the cultured mouse erythroid progenitors with and without the blocking of nuclear opening during differentiation. We found that terminal differentiation from the basophilic to orthochromatic stages of erythroblasts involves compaction and establishment of long-range interactions of the heterochromatin regions, which is associated with globally increased accessibility and upregulation of erythroid-related genes. Surprisingly, blocking of nuclear opening did not have a significant impact on 3D genomic organization, chromatin accessibility, or transcriptome despite the inhibition of histone release and nuclear condensation. Inhibition of nuclear opening also significantly affected enucleation. We further demonstrated this through a caspase-3 and 7 double knockout mouse model, which showed significant defects in nuclear opening and condensation with a compromise of enucleation in fetal erythroid progenitors. However, loss of these effector caspases had minimal effects on the red cell indices and survival of the recipient animals in a fetal liver cell transplantation model. Overall, these results indicate that nuclear opening and histone release may not be necessary for chromatin condensation and global transcriptome but are critical for nuclear condensation and efficient enucleation. These data also underline the robustness of enucleation despite the dysplastic or less condensed nucleus.
2022-12-16 | GSE185469 | GEO
Project description:Mammalian terminal erythropoiesis involves chromatin and nuclear condensation followed by enucleation. Late-stage erythroblasts undergo caspase-mediated nuclear opening formation that is important for nuclear condensation through partial release of histones. It remains unknown whether nuclear opening and histone release influence the three-dimensional (3D) genomic organization during terminal erythropoiesis. Here, we compared the genome wide 3D organization, chromatin accessibility, and transcriptome of the cultured mouse erythroid progenitors with and without the blocking of nuclear opening during differentiation. We found that terminal differentiation from the basophilic to orthochromatic stages of erythroblasts involves compaction and establishment of long-range interactions of the heterochromatin regions, which is associated with globally increased accessibility and upregulation of erythroid-related genes. Surprisingly, blocking of nuclear opening did not have a significant impact on 3D genomic organization, chromatin accessibility, or transcriptome despite the inhibition of histone release and nuclear condensation. Inhibition of nuclear opening also significantly affected enucleation. We further demonstrated this through a caspase-3 and 7 double knockout mouse model, which showed significant defects in nuclear opening and condensation with a compromise of enucleation in fetal erythroid progenitors. However, loss of these effector caspases had minimal effects on the red cell indices and survival of the recipient animals in a fetal liver cell transplantation model. Overall, these results indicate that nuclear opening and histone release may not be necessary for chromatin condensation and global transcriptome but are critical for nuclear condensation and efficient enucleation. These data also underline the robustness of enucleation despite the dysplastic or less condensed nucleus.
2022-12-16 | GSE185468 | GEO
Project description:Mammalian terminal erythropoiesis involves chromatin and nuclear condensation followed by enucleation. Late-stage erythroblasts undergo caspase-mediated nuclear opening formation that is important for nuclear condensation through partial release of histones. It remains unknown whether nuclear opening and histone release influence the three-dimensional (3D) genomic organization during terminal erythropoiesis. Here, we compared the genome wide 3D organization, chromatin accessibility, and transcriptome of the cultured mouse erythroid progenitors with and without the blocking of nuclear opening during differentiation. We found that terminal differentiation from the basophilic to orthochromatic stages of erythroblasts involves compaction and establishment of long-range interactions of the heterochromatin regions, which is associated with globally increased accessibility and upregulation of erythroid-related genes. Surprisingly, blocking of nuclear opening did not have a significant impact on 3D genomic organization, chromatin accessibility, or transcriptome despite the inhibition of histone release and nuclear condensation. Inhibition of nuclear opening also significantly affected enucleation. We further demonstrated this through a caspase-3 and 7 double knockout mouse model, which showed significant defects in nuclear opening and condensation with a compromise of enucleation in fetal erythroid progenitors. However, loss of these effector caspases had minimal effects on the red cell indices and survival of the recipient animals in a fetal liver cell transplantation model. Overall, these results indicate that nuclear opening and histone release may not be necessary for chromatin condensation and global transcriptome but are critical for nuclear condensation and efficient enucleation. These data also underline the robustness of enucleation despite the dysplastic or less condensed nucleus.
2022-12-16 | GSE184974 | GEO
Project description:To determine the physiological targets of the NELF complex, and provide insight into the mechanism of NELF activity in vivo. Keywords: gene expression, transcription elongation, stress response
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Project description:NELF-A phosphorylation by P-TEFb is a key event in the pausing release. We conduct IMAC-LC-MS-MS to identified NELF-A phosphorylation site by activation P-TEFb kinase.
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