Spatiotemporal regulation of liquid-like condensates in epigenetic inheritance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA439309 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6871270.fastq.gz | Fastqsanger.gz | |||
| SRR6871261.fastq.gz | Fastqsanger.gz | |||
| SRR6871271.fastq.gz | Fastqsanger.gz | |||
| SRR6871262.fastq.gz | Fastqsanger.gz | |||
| SRR6871272.fastq.gz | Fastqsanger.gz |
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Project description:Non-membrane bound organelles such as nucleoli, processing bodies, cajal bodies, and germ granules form via spontaneous self-assembly of specific proteins and RNAs. How these biomolecular condensates form and interact are poorly understood. Here we identify two proteins (ZNFX-1 and WAGO-4) that localize to C. elegans germ granules (P granules) in early germline blastomeres. Later in germline development, ZNFX-1/WAGO-4 separate from P granules to define an independent liquid-like condensate that we term the Z granule. In adult germ cells, Z granules assemble into ordered tri-droplet assemblages with P granules and Mutator foci that we term the PZM granule. Finally, we show that one biological function of ZNFX-1 and WAGO-4 is to interact with RNAs in the C. elegans germline to promote transgenerational epigenetic inheritance (TEI). We speculate that the temporal and spatial ordering of liquid droplet organelles may help cells organize and coordinate the complex RNA processing pathways underlying gene regulatory systems, such as RNA-directed TEI.
2018-03-21 | GSE112109 | GEO
Project description:Non-membrane-bound organelles such as nucleoli, processing bodies, Cajal bodies and germ granules form by the spontaneous self-assembly of specific proteins and RNAs. How these biomolecular condensates form and interact is poorly understood. Here we identify two proteins, ZNFX-1 and WAGO-4, that localize to Caenorhabditis elegans germ granules (P granules) in early germline blastomeres. Later in germline development, ZNFX-1 and WAGO-4 separate from P granules to define an independent liquid-like condensate that we term the Z granule. In adult germ cells, Z granules assemble into ordered tri-condensate assemblages with P granules and Mutator foci, which we term PZM granules. Finally, we show that one biological function of ZNFX-1 and WAGO-4 is to interact with silencing RNAs in the C. elegans germline to direct transgenerational epigenetic inheritance. We speculate that the temporal and spatial ordering of liquid droplet organelles may help cells to organize and coordinate the complex RNA processing pathways that underlie gene-regulatory systems, such as RNA-directed transgenerational epigenetic inheritance.
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Project description:Transgenerational epigenetic inheritance (TEI) describes the transmission of gene-regulatory information across generations without altering DNA sequences. TEI allows priming of offspring towards changing environmental conditions and plays a role in the maintenance of gene silencing of selfish genetic elements like transposons. Small regulatory RNAs are well known to act in TEI, and can be transmitted via the male. Such inheritance via sperm requires dedicated mechanisms, as much of the cellular content is extruded during spermatogenesis. We identify a phase separation-based mechanism, which couples the paternal inheritance of a specific small RNA-bound silencing factor via S-palmitoylation to the transport of membranous organelles. Our findings uncover a thus far unknown paternal TEI mechanism, and describe a novel mode of transport of phase-separated condensates.
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Project description:Chromatin-based epigenetic memory relies on the equal distribution of parental histone tetramers, which serve as templates for duplicating parental chromatin, to newly synthesized daughter DNA strands. Histone chaperones within the replisome, such as the histone binding domains (HBDs) of Mcm2 and Pol alpha, are critical for transferring parental histones to the lagging strand. However, the mechanisms and impact of parental histone transfer on epigenetic inheritance remain debated. Using fission yeast heterochromatin assembly as a model, we discovered that replisome component Mrc1 is crucial for both epigenetic inheritance and transfer of parental histones to the lagging strand, akin to a Mcm2-HBD mutation. Isolation of separation-of-function mutations revealed that Mrc1s role in epigenetic inheritance is distinct form its DNA replication checkpoint and replisome speed control functions. Instead, Mrc1 prevents undesirable replisome interactions to facilitate interactions between Mcm2 and Pol alpha for the proper passage of parental histones. These findings unveil a novel function of Mrc1 and underscore the critical role of parental histone segregation in epigenetic inheritance.
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Project description:Alpha-thalassemia X-linked intellectual disability syndrome (ATR-X) is caused by mutations in the ATRX gene, which plays a pivotal role in heterochromatin integrity. In this study, we uncover a novel mechanism by which ATRX influences fate of human neural progenitor cells (hNPCs) through the formation of liquid-liquid phase separation (LLPS)-driven condensates. We discovered that the intrinsically disordered region (IDR) of ATRX is essential for driving LLPS, enabling ATRX to form dynamic condensates within the nucleus. The IDR region can autonomously form phase-separated droplets and recruit co-activators. In addition, formation of these condensates was crucial for the localization of ATRX at super-enhancers (SEs) in hNPCs, directly linking ATRX condensate dynamics to the regulation of gene expression critical for neural differentiation. Disruption of ATRX condensates leads to impaired neuronal differentiation, emphasizing the functional significance of ATRX in human neural development. Our findings provide new insights into the molecular function of ATRX beyond its established roles in chromatin structure, and suggest that LLPS is a key regulatory mechanism through which ATRX supports neurodevelopment. This study opens avenues for further exploration of how dysregulation of ATRX and its phase-separation ability may contribute to the pathogenesis of ATR-X syndrome and related neurodevelopmental disorders.
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Project description:Alpha-thalassemia X-linked intellectual disability syndrome (ATR-X) is caused by mutations in the ATRX gene, which plays a pivotal role in heterochromatin integrity. In this study, we uncover a novel mechanism by which ATRX influences fate of human neural progenitor cells (hNPCs) through the formation of liquid-liquid phase separation (LLPS)-driven condensates. We discovered that the intrinsically disordered region (IDR) of ATRX is essential for driving LLPS, enabling ATRX to form dynamic condensates within the nucleus. The IDR region can autonomously form phase-separated droplets and recruit co-activators. In addition, formation of these condensates was crucial for the localization of ATRX at super-enhancers (SEs) in hNPCs, directly linking ATRX condensate dynamics to the regulation of gene expression critical for neural differentiation. Disruption of ATRX condensates leads to impaired neuronal differentiation, emphasizing the functional significance of ATRX in human neural development. Our findings provide new insights into the molecular function of ATRX beyond its established roles in chromatin structure, and suggest that LLPS is a key regulatory mechanism through which ATRX supports neurodevelopment. This study opens avenues for further exploration of how dysregulation of ATRX and its phase-separation ability may contribute to the pathogenesis of ATR-X syndrome and related neurodevelopmental disorders.
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Project description:ATRX Condensates Formed by Liquid-Liquid Phase Separation Regulate Neural Progenitor Cell Identity
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Project description:Biomolecular condensates, such as stress and germ granules, often contain sub-compartments. For instance, the Caenorhabditis elegans germ granule, which localizes near the outer nuclear membrane of germ cell nuclei, is composed of at least four ordered compartments, each housing distinct sets of proteins and RNAs. How these compartments form and why they are spatially ordered remains poorly understood. Here, we show that the conserved RNA helicase DDX-19 defines another compartment of the larger C. elegans germ granule, which we term the D compartment. The D compartment exhibits properties of a liquid condensate and forms between the outer nuclear pore filament and other compartments of the germ granule. Two nuclear pore proteins, NPP-14 and GLEL-1, are required for its formation, suggesting that the D compartment localizes adjacent to the outer nuclear membrane via interactions with the nuclear pore. The loss of DDX-19, NPP-14, or GLEL-1 leads to functional defects, including aberrant formation of the other four germ granule compartments, a loss of germline immortality, and dysregulation of small RNA-based transgenerational epigenetic inheritance programs. Hence, we propose that a function of the D compartment is to anchor larger germ granules to nuclear pores, enabling germ granule compartmentalization and promoting transgenerational RNA surveillance.
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Project description:ATRX Condensates Formed by Liquid-Liquid Phase Separation Regulate Neural Progenitor Cell Identity (RNA)
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