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A mechanically regulated liquid-liquid phase separation of the transcriptional regulator Tono instructs muscle development

ABSTRACT: A mechanically regulated liquid-liquid phase separation of the transcriptional regulator Tono instructs muscle development

PROVIDER: PRJNA1128179 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29550802.fastq.gz	Fastqsanger.gz
	SRR29550803.fastq.gz	Fastqsanger.gz
	SRR29550804.fastq.gz	Fastqsanger.gz
	SRR29550805.fastq.gz	Fastqsanger.gz
	SRR29550806.fastq.gz	Fastqsanger.gz

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A mechanically regulated liquid-liquid phase separation of the transcriptional regulator Tono instructs muscle development

Project description:Muscle morphogenesis is a multi-step program, starting with myoblast fusion, followed by myotube-tendon attachment and sarcomere assembly, with subsequent sarcomere maturation, mitochondrial amplification and specialisation. The correct chronological order of these steps requires precise control of the transcriptional regulators and their effectors. How this regulation is achieved during muscle development is not well understood. In a genome-wide RNAi screen inDrosophila, we identified the BTB-zinc finger protein Tono (CG32121) as a muscle-specific transcriptional regulator.tonomutant flight muscles display severe deficits in mitochondria and sarcomere maturation, resulting in uncontrolled contractile forces causing muscle atrophy during development. Tono protein is expressed during sarcomere maturation and localises in distinct condensates in flight muscle nuclei. Interestingly, internal pressure exerted by the maturing sarcomeres deforms the muscle nuclei into elongated shapes and changes the Tono condensates, suggesting that Tono senses the mechanical status of the muscle cells. Indeed, external mechanical pressure on the muscles triggers rapid liquid-liquid phase separation of Tono utilising its BTB domain. Thus, we propose that Tono senses high mechanical pressure to in turn adapt muscle transcription specifically at the sarcomere maturation stage. Consistently,tonomutant muscles display specific defects in a transcriptional switch that represses early muscle differentiation genes and boosts late ones. We hypothesise that a similar mechano-responsive regulation mechanism may control the activity of related BTB-zinc finger proteins that, if mutated, can result in uncontrolled force production in human muscle.

2024-06-30 | GSE270794 | GEO

Bacterial Heterochromatin Formation Through Liquid-Liquid Phase Separation

Project description:Bacterial Heterochromatin Formation Through Liquid-Liquid Phase Separation

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HSD17B13 liquid-liquid phase separation activates autocrine platelet-activating factor signaling in NASH

Project description:HSD17B13 liquid-liquid phase separation activates autocrine platelet-activating factor signaling in NASH

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HSD17B13 liquid-liquid phase separation activates autocrine platelet-activating factor signaling in NASH

Project description:Loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) are associated with decreased inflammation in human chronic liver disease. The underlying mechanism by which HSD17B13 promotes liver inflammation remains largely elusive. Here we find that HSD17B13 undergoes liquid-liquid phase separation (LLPS) around lipid droplets (LDs) in the liver of NASH patients. Dimerization of HSD17B13 drives LLPS formation and regulates its enzyme activity. HSD17B13 LLPS promotes leukocyte adhesion and fibrinogen expression in hepatocytes via activating autocrine platelet activating factor (PAF) signaling. Importantly, adeno-associated viral (AAV)-mediated xeno-expression of human HSD17B13 promotes liver inflammation in Hsd17b13-/- mice induced by high fat diet/carbon tetrachloride treatment. In conclusion, HSD17B13 LLPS triggers liver inflammation via promoting PAF-mediated leukocyte adhesion. Targeting HSD17B13 phase transition would be a promising approach to treat liver inflammation in chronic liver disease.

2024-12-19 | GSE238060 | GEO

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [RNA-seq]

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

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [ChIP-seq]

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2021-10-06 | GSE148933 | GEO

Suppression of liquid-liquid phase separation by 1,6-hexanediol partially compromises the 3D genome organization in living cells

Project description:Liquid-liquid phase separation (LLPS) contributes to the spatial and functional segregation of molecular processes within the cell nucleus. However, the role played by LLPS in chromatin folding in living cells remains unclear. Here, using stochastic optical reconstruction microscopy (STORM) and Hi-C techniques, we studied the effects of 1,6-hexanediol (1,6-HD)- mediated LLPS disruption/modulation on higher-order chromatin organization in living cells. We found that 1,6-HD treatment caused the enlargement of nucleosome clutches and their more uniform distribution in the nuclear space. At a megabase-scale, chromatin underwent moderate but irreversible perturbations that resulted in the partial mixing of A and B compartments. The removal of 1,6-HD from the culture medium did not allow chromatin to acquire initial configurations, and resulted in more compact repressed chromatin than in untreated cells. 1,6-HD treatment also weakened enhancer-promoter interactions and TAD insulation but did not considerably affect CTCF-dependent loops. Our results suggest that 1,6-HD-sensitive LLPS plays a limited role in chromatin spatial organization by constraining its folding patterns and facilitating compartmentalization at different levels.

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