Bacterial Heterochromatin Formation Through Liquid-Liquid Phase Separation
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ABSTRACT:
PROVIDER: PRJNA730564 | ENA |
REPOSITORIES: ENA
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Project description:Heterochromatin is most often associated with eukaryotic organisms. Yet, bacteria also contain areas with densely protein-occupied chromatin that silences gene expression. One nucleoid-associated silencing factor is Hfq, which is strongly enriched at prophages and mobile genetic elements. Here we demonstrate that polyphosphate, an ancient and highly conserved polyanion, is essential for the specific binding of Hfq to these regions. Lack of either polyphosphate or Hfq causes unsolicited prophage and transposon mobilization, which drastically increases mutagenesis. We discovered that Hfq and polyphosphate form high molecular weight complexes that interact with DNA in phase-separated viscous condensates. We propose that polyP provides a scaffold that promotes Hfq binding to DNA regions with high intrinsic curvature, and thus serves as one hitherto unknown driver of heterochromatin formation in bacteria.
2021-12-23 | GSE174575 | GEO
Project description:Liquid-liquid phase separation has drawn great attention as a physical process that mediates the formation of membraneless organelles in cells to coordinate biological reactions in space and time. Previously, it was proposed that the formation of phase-separated droplets is a unique property of HP1α. Here, we show that HP1β, but not HP1α and HP1ɤ, forms nucleosome dependent phase separated droplets. We demonstrate that H3K9me3 is required for HP1β dependent phase separation. Importantly, HP1β dependent phase separation regulates heterochromatin formation, thus controlling embryonic stem cells differentiation. In response to pluripotency exit, HP1β is phosphorylated at serine 89 recruiting KAP1, a pluripotency regulator, and sequestering it in the heterochromatin compartment. This induces changes in the level of pluripotency factors and triggers pluripotency exit. We propose that such a trapping mechanism creates a fast and dynamic mode of remote control of gene expression to regulate cell fate decisions solely based on membraneless organelles.
2022-05-01 | E-MTAB-8329 | biostudies-arrayexpress
Project description:Eukaryotic chromosomes fold into topologically associating domains (TADs), which further gather in active (A) or inactive (B) genomic compartments. Here we show that Scaffold Attachment Factor B (SAFB), a nuclear matrix-associated protein with RNA binding functions, modulates global chromatin condensation in a dosage-dependent manner. Upon the depletion of SAFB, the genome coverage of Lamina-associated-domains (LADs) decreases from 53.33% to 45.93%, and both inter- and intra-TAD chromatin-chromatin interactions in compartment B decrease significantly. In the nucleus, SAFB favorably co-localizes with H3K9me3, a marker of heterochromatin, and the disruption of SAFB leads to a collapse of H3K9me3 foci. Furthermore, we show that SAFB proteins can form liquid-liquid phase separation in the cell and in vitro. Intriguingly, SAFB interacts with RNAs from repetitive elements enriched in heterochromatin (e.g., Major Satellites and LINE1), which can promote SAFB-mediated phase separation, depending on the density of SAFB recognizing motifs in the RNAs.
2019-12-01 | GSE141113 | GEO
Project description:Eukaryotic chromosomes fold into topologically associating domains (TADs), which further gather in active (A) or inactive (B) genomic compartments. Here we show that Scaffold Attachment Factor B (SAFB), a nuclear matrix-associated protein with RNA binding functions, modulates global chromatin condensation in a dosage-dependent manner. Upon the depletion of SAFB, the genome coverage of Lamina-associated-domains (LADs) decreases from 53.33% to 45.93%, and both inter- and intra-TAD chromatin-chromatin interactions in compartment B decrease significantly. In the nucleus, SAFB favorably co-localizes with H3K9me3, a marker of heterochromatin, and the disruption of SAFB leads to a collapse of H3K9me3 foci. Furthermore, we show that SAFB proteins can form liquid-liquid phase separation in the cell and in vitro. Intriguingly, SAFB interacts with RNAs from repetitive elements enriched in heterochromatin (e.g., Major Satellites and LINE1), which can promote SAFB-mediated phase separation, depending on the density of SAFB recognizing motifs in the RNAs.
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Project description:Eukaryotic chromosomes fold into topologically associating domains (TADs), which further gather in active (A) or inactive (B) genomic compartments. Here we show that Scaffold Attachment Factor B (SAFB), a nuclear matrix-associated protein with RNA binding functions, modulates global chromatin condensation in a dosage-dependent manner. Upon the depletion of SAFB, the genome coverage of Lamina-associated-domains (LADs) decreases from 53.33% to 45.93%, and both inter- and intra-TAD chromatin-chromatin interactions in compartment B decrease significantly. In the nucleus, SAFB favorably co-localizes with H3K9me3, a marker of heterochromatin, and the disruption of SAFB leads to a collapse of H3K9me3 foci. Furthermore, we show that SAFB proteins can form liquid-liquid phase separation in the cell and in vitro. Intriguingly, SAFB interacts with RNAs from repetitive elements enriched in heterochromatin (e.g., Major Satellites and LINE1), which can promote SAFB-mediated phase separation, depending on the density of SAFB recognizing motifs in the RNAs.
2019-12-01 | GSE141080 | GEO
Project description:Eukaryotic chromosomes fold into topologically associating domains (TADs), which further gather in active (A) or inactive (B) genomic compartments. Here we show that Scaffold Attachment Factor B (SAFB), a nuclear matrix-associated protein with RNA binding functions, modulates global chromatin condensation in a dosage-dependent manner. Upon the depletion of SAFB, the genome coverage of Lamina-associated-domains (LADs) decreases from 53.33% to 45.93%, and both inter- and intra-TAD chromatin-chromatin interactions in compartment B decrease significantly. In the nucleus, SAFB favorably co-localizes with H3K9me3, a marker of heterochromatin, and the disruption of SAFB leads to a collapse of H3K9me3 foci. Furthermore, we show that SAFB proteins can form liquid-liquid phase separation in the cell and in vitro. Intriguingly, SAFB interacts with RNAs from repetitive elements enriched in heterochromatin (e.g., Major Satellites and LINE1), which can promote SAFB-mediated phase separation, depending on the density of SAFB recognizing motifs in the RNAs.
2019-12-01 | GSE141104 | GEO
Project description:CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.
2023-11-08 | GSE243423 | GEO
Project description:CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.
2023-11-08 | GSE243422 | GEO
Project description:Components of the transcription machinery can undergo liquid-liquid phase separation, but the functional importance of phase-separated condensates in transcriptional control is not well understood. Here we report that disease-causing mutations in several transcription factors (TFs) alter the phase separation capacity of those TFs. We first demonstrate that the Hoxd13 TF, and its intrinsically disordered N-terminus form phase-separated condensates. Expansions of a polyalanine repeat, which cause hereditary synpolydactyly in humans, facilitate phase separation of Hoxd13, and alter the transcriptional program of several cell types in a cell-specific manner in vivo. Disease-associated expansions of aminoacid repeats in intrinsically disordered regions of other TFs were similarly found to alter phase separation. These results suggest that aberrant phase separation of transcriptional regulators may underlie a spectrum of human pathologies. The paper is available at https://doi.org/10.1016/j.cell.2020.04.018
2020-05-07 | GSE128818 | GEO
Project description:HIPPO-YAP/TAZ signaling has been implicated in supratentorial ependymoma formation from neural progenitor cells (NPC) in the brain, however, the underlying mechanisms to trigger the neural progenitor cell transformation remains elusive. Here, we uncover that patient-derived tumorigenic YAP-fusion proteins (YAP-MAMLD1 and C11ORF95-YAP) promote ependymoma tumorigenesis through forming liquid-liquid phase-separated condensates. Intrinsically disordered regions (IDR) in the fusion proteins promote oligomerization of YAP-transcriptional co-activators and self-assembly of nuclear puncta-like membrane-less organelles. Phase separation of YAP-fusion proteins further facilitates the compartmentalization of transcriptional coactivators, BRD4 and MED1, resulting in pervasive enhancer landscape changes and exclusion of transcriptional repressors such as PRC2 complexes. YAP-fusion proteins-induced nuclear puncta recruit RNA polymerase II to promote transcriptional bursting of multiple oncogenic pathways. Moreover, we show that IDR-mediated phase separation is necessary for YAP-fusion protein-induced tumor formation. Distinct YAP fusion-proteins identified in other human tumors also encompass IDR features. Together, our data suggest that IDR-mediated phase separation is an integral component of YAP-fusion protein-induced tumorigenesis and might serve as a therapeutic target in supratentorial ependymoma.
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