A DNA Repair Pathway Can Regulate Transcriptional Noise to Promote Cell Fate Transitions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA734629 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14713300.fastq.gz | Fastqsanger.gz | |||
| SRR14713301.fastq.gz | Fastqsanger.gz | |||
| SRR14713302.fastq.gz | Fastqsanger.gz | |||
| SRR14713303.fastq.gz | Fastqsanger.gz | |||
| SRR14713304.fastq.gz | Fastqsanger.gz |
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Project description:Stochastic fluctuations in gene expression (‘noise’) are often considered detrimental but, in many disciplines, fluctuations are exploited for benefit (e.g., dither). We show here that DNA base-excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA-repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean-expression levels. This amplified expression noise originates from shorter duration, higher intensity, transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels and this mechanism, which we term Discordant Transcription through Repair (DiThR), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.
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Project description:Stochastic fluctuations in gene expression ("noise") are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean expression levels. This amplified expression noise originates from shorter-duration, higher-intensity transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we refer to as "discordant transcription through repair" ("DiThR," which is pronounced "dither"), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.
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Project description:Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although the signaling circuits and gene regulatory networks regulating pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological transitions and mechanical deformations that occur during state transitions remains a fundamental open question. Here, we discover that stem cell fate transitions are gated by two critical signals - nuclear envelope fluctuations and osmotic stress - that emanate from growth factor signaling-controlled changes in nuclear volume and nucleoplasm viscosity/density to subsequently trigger changes in nuclear architecture and transcription. We observe that fate transitions in the early human embryo and in an in vitro model of exit from pluripotency are associated with rapid changes in nuclear volume and nuclear envelope mechanics. These changes alter nuclear mechanosensitivity and trigger changes in nucleoplasmic viscosity and nuclear condensates to prime chromatin for a cell fate transition. However, while this mechanical priming accelerates fate transitions, sustained biochemical signals are required for efficient induction of differentiation. Our findings establish a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signaling and chromatin state to control cell fate transition dynamics.
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Project description:Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although the signaling circuits and gene regulatory networks regulating pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological transitions and mechanical deformations that occur during state transitions remains a fundamental open question. Here, we discover that stem cell fate transitions are gated by two critical signals - nuclear envelope fluctuations and osmotic stress - that emanate from growth factor signaling-controlled changes in nuclear volume and nucleoplasm viscosity/density to subsequently trigger changes in nuclear architecture and transcription. We observe that fate transitions in the early human embryo and in an in vitro pluripotency exit model are guided by rapid changes in nuclear volume and nuclear envelope mechanics. These changes alter nuclear mechanosensitivity and trigger changes in nucleoplasmic viscosity and nuclear condensates that together prime chromatin for a cell fate transition. However, while this mechanical priming accelerates fate transitions, sustained biochemical signals are required for robust induction of differentiation. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signaling and chromatin state to control cell fate transition dynamics.
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Project description:Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although the signaling circuits and gene regulatory networks regulating pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological transitions and mechanical deformations that occur during state transitions remains a fundamental open question. Here, we discover that stem cell fate transitions are gated by two critical signals - nuclear envelope fluctuations and osmotic stress - that emanate from growth factor signaling-controlled changes in nuclear volume and nucleoplasm viscosity/density to subsequently trigger changes in nuclear architecture and transcription. We observe that fate transitions in the early human embryo and in an in vitro pluripotency exit model are guided by rapid changes in nuclear volume and nuclear envelope mechanics. These changes alter nuclear mechanosensitivity and trigger changes in nucleoplasmic viscosity and nuclear condensates that together prime chromatin for a cell fate transition. However, while this mechanical priming accelerates fate transitions, sustained biochemical signals are required for robust induction of differentiation. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signaling and chromatin state to control cell fate transition dynamics.
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Project description:Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although the signaling circuits and gene regulatory networks regulating pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological transitions and mechanical deformations that occur during state transitions remains a fundamental open question. Here, we discover that stem cell fate transitions are gated by two critical signals - nuclear envelope fluctuations and osmotic stress - that emanate from growth factor signaling-controlled changes in nuclear volume and nucleoplasm viscosity/density to subsequently trigger changes in nuclear architecture and transcription. We observe that fate transitions in the early human embryo and in an in vitro pluripotency exit model are guided by rapid changes in nuclear volume and nuclear envelope mechanics. These changes alter nuclear mechanosensitivity and trigger changes in nucleoplasmic viscosity and nuclear condensates that together prime chromatin for a cell fate transition. However, while this mechanical priming accelerates fate transitions, sustained biochemical signals are required for robust induction of differentiation. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signaling and chromatin state to control cell fate transition dynamics.
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