Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA876259 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21403323_1.fastq.gz | Fastqsanger.gz | |||
| SRR21403323_2.fastq.gz | Fastqsanger.gz | |||
| SRR21403324_1.fastq.gz | Fastqsanger.gz | |||
| SRR21403324_2.fastq.gz | Fastqsanger.gz | |||
| SRR21403924_subreads.fastq.gz | Fastqsanger.gz |
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Project description:Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA
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Project description:Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at near single-nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with most nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication components and selectively form a triple-stranded displacement loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, acting consistently with a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.
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Project description:Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at near single-nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with most nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication components and selectively form a triple-stranded displacement loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, acting consistently with a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.
2023-11-13 | GSE212611 | GEO
Project description:Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet how mtDNA is packaged into individual mitochondrial nucleoids remains poorly resolved, as mitochondria lack histones or other chromatin machinery important for nuclear genome compaction. Here, we used long-read single-molecule accessibility mapping to resolve the compaction of individual full-length mitochondrial nucleoids at single-nucleotide resolution. We find that, unlike the nuclear genome, human mtDNA largely undergoes an all-or-none global compaction, with the majority of nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are occupied by transcription and replication machinery, and selectively form a D-loop structure. In addition, we demonstrate that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, and acts via a ‘nucleation and spreading’ mechanism to coat and compact mitochondrial nucleoids. Overall, these findings expose the primary architecture of mtDNA packaging and regulation in humans.
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Project description:Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at near single-nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with most nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication components and selectively form a triple-stranded displacement loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, acting consistently with a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.
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Project description:Heterogeneous single-molecule packaging of human mitochondrial nucleoids
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Project description:Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor a), including expression of specific ESR1 variants is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males, and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.
2024-10-30 | GSE280715 | GEO
Project description:Nucleoid remodeling facilitated by DNA supercoiling results in changes in nucleoid configuration and involves nucleoid-associated proteins (NAPs) and structural maintenance of chromosomes (SMC) proteins among others. Changes in nucleoid configurations regulated by NAPs are synchronized with cellular adaptation and influence the simultaneous expression of several genes. HU, a ubiquitous bacterial histone-like protein, is among the most conserved and abundant NAPs in eubacteria. In Escherichia coli, HU forms dimers by HUα self-association (HUαα) or by HUα-HUβ interactions (HUαβ). HUα is mostly expressed during lag and early exponential growth phase and HUβ is expressed only during the later exponential and stationary phase, pointing to distinct HUαα/DNA and HUαβ/DNA packaging of the nucleoid in regulating expression patterns during growth and stasis. Mutations or the deletion of HU transform the E. coli nucleoid to a different form and alter overall transcription program; thus, HU interactions with DNA directly affect global gene regulation. Recently, analysis of high-resolution contact maps of the E. coli nucleoid revealed an important role of HU to promote long-range DNA-DNA contacts within the nucleoid. Yet, the molecular connections between HU-DNA interactions and changes in nucleoid architecture that regulate gene expression globally remain unknown. Here, we explored the higher-order E. coli nucleoid organization by soft x-ray tomography (SXT) and revealed an effect of HU surface charges in overall nucleoid organization and rearrangements. We also studied global transcription by next-generation RNA sequencing (RNA-Seq) and found a link between nucleoid rearrangement and changes in global transcription. To determine the functional relationships of observed nucleoid rearrangement and HU-DNA interactions, we also characterized the overall organization of HU nucleoprotein complexes in solution by small angle x-ray scattering (SAXS). We found that HUαα-mediated DNA networks are different at different ionic strengths and pHs. By means of macromolecular crystallography, we additionally elucidate HUαα dependent molecular switches that modulate DNA networking. This integrative structural study explains how HUαα regulates dynamic transformations of the nucleoid by DNA bridging to control nucleoid rearrangement and global gene regulation.
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