ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing
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ABSTRACT:
PROVIDER: PRJNA623501 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11496500.fastq.gz | Fastqsanger.gz | |||
| SRR11496501.fastq.gz | Fastqsanger.gz | |||
| SRR11496502.fastq.gz | Fastqsanger.gz | |||
| SRR11496503.fastq.gz | Fastqsanger.gz | |||
| SRR11496504.fastq.gz | Fastqsanger.gz |
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Project description:Members of the mammalian AlkB family are known to mediate nucleic acid demethylation. ALKBH7, a mammalian AlkB homologue, localizes in mitochondria (mt) and affects metabolism, but its function and mechanism of action are unknown. Here, we report an approach to site-specifically detect m1A, m3C, m1G, and m22G modifications simultaneously within all cellular RNAs, and discovered that human ALKBH7 demethylates N2, N2-dimethylguanosine (m22G) and N1-methyladenosine (m1A) within mt-Ile and mt-Leu1 pre-tRNA regions, respectively, in nascent polycistronic mt-RNA. We further show that ALKBH7 regulates the processing and structural dynamics of polycistronic mt-RNAs. Depletion of ALKBH7 leads to increased polycistronic mt-RNA processing, reduced steady-state mitochondria-encoded tRNA levels and protein translation, as well as notably decreased mitochondrial activity. Thus, we identify ALKBH7 as an RNA demethylase that controls nascent mt-RNA processing and mitochondrial activity.
2021-06-02 | GSE148202 | GEO
Project description:Members of the mammalian AlkB family are known to mediate nucleic acid demethylation1,2. ALKBH7, a mammalian AlkB homologue, localizes in mitochondria and affects metabolism3, but its function and mechanism of action are unknown. Here we report an approach to site-specifically detect N1-methyladenosine (m1A), N3-methylcytidine (m3C), N1-methylguanosine (m1G) and N2,N2-dimethylguanosine (m22G) modifications simultaneously within all cellular RNAs, and discovered that human ALKBH7 demethylates m22G and m1A within mitochondrial Ile and Leu1 pre-tRNA regions, respectively, in nascent polycistronic mitochondrial RNA4-6. We further show that ALKBH7 regulates the processing and structural dynamics of polycistronic mitochondrial RNAs. Depletion of ALKBH7 leads to increased polycistronic mitochondrial RNA processing, reduced steady-state mitochondria-encoded tRNA levels and protein translation, and notably decreased mitochondrial activity. Thus, we identify ALKBH7 as an RNA demethylase that controls nascent mitochondrial RNA processing and mitochondrial activity.
| S-EPMC8716185 | biostudies-literature
Project description:The human mitochondrial genome comprises a distinct genetic system transcribed as precursor polycistronic transcripts that are subsequently cleaved to generate individual mRNAs, tRNAs and rRNAs. Here we provide a comprehensive analysis of the human mitochondrial transcriptome across multiple cell lines and tissues. Using directional deep sequencing and parallel analysis of RNA ends, we demonstrate wide variation in mitochondrial transcript abundance, and precisely resolve transcript processing and maturation events. We identify novel transcripts, including small RNAs, and observe the enrichment of several nuclear RNAs in mitochondria. Using high-throughput in vivo DNaseI footprinting, we establish the global profile of DNA-binding protein occupancy across the mitochondrial genome at single nucleotide resolution, revealing novel regulatory features at mitochondrial transcription initiation sites and functional insights into disease-associated variants. Together, this integrated analysis of the mitochondrial transcriptome reveals unexpected complexity in the regulation, expression, and processing of mitochondrial RNA, and itM-CM-^BM-BM- provides a resource for the future study of mitochondrial function (accessed at mitochondria.matticklab.com). Examination of the mitochondiral transcriptome by long and small RNA sequencing, PARE sequencing and DNAseI hypersensitivity mapping.
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Project description:How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in human and other animals were strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene-gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages, but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene body and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand specific non-CpG methylation, its dynamic regulation and its impact on the polycistronic mitochondrial transcript processing.
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Project description:How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in human and other animals were strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene-gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages, but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene body and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand specific non-CpG methylation, its dynamic regulation and its impact on the polycistronic mitochondrial transcript processing.
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Project description:How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in human and other animals were strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene-gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages, but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene body and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand specific non-CpG methylation, its dynamic regulation and its impact on the polycistronic mitochondrial transcript processing.
2019-08-22 | GSE133961 | GEO
Project description:How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in human and other animals were strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene-gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages, but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene body and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand specific non-CpG methylation, its dynamic regulation and its impact on the polycistronic mitochondrial transcript processing.
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Project description:How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in human and other animals were strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene-gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages, but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene body and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand specific non-CpG methylation, its dynamic regulation and its impact on the polycistronic mitochondrial transcript processing.
2019-08-22 | GSE133960 | GEO
Project description:How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in human and other animals were strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene-gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages, but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene body and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand specific non-CpG methylation, its dynamic regulation and its impact on the polycistronic mitochondrial transcript processing.
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Project description:In animals the organization of the compact mitochondrial genome and lack of introns have necessitated a unique mechanism for RNA processing. To date the regulation of mitochondrial RNA processing and its importance for ribosome biogenesis and energy metabolism are not clear. To understand the in vivo role of the endoribonuclease component of the RNase P complex, MRPP3, we created conditional knockout mice. Here we show that MRPP3 is essential for life, and heart and skeletal muscle-specific knockout leads to a cardiomyopathy early in life, indicating that it is the only RNase P enzyme in mitochondria. We show that RNA processing is required for the biogenesis of the respiratory chain and mitochondrial function. Transcriptome-wide parallel analyses of RNA ends (PARE) and RNA-Seq enabled us to identify the in vivo cleavage sites of RNase P. Cleavage of the 5â² tRNA ends precedes 3â² end processing in vivo and is required for the correct biogenesis of the mitochondrial ribosomal subunits and mitoribosomal proteins that are differentially stabilized or degraded in the absence of mature rRNAs. Finally we identify that large mitoribosomal proteins can form a subcomplex on a precursor mt-RNA containing the 16S rRNA indicating that mitoribosomal biogenesis proceeds co-transcriptionally. Taken together our data show that RNA processing links transcription to translation via assembly of the mitoribosome. Total RNA was isolated from heart tissue from 11 week old control (Mrpp3loxP/loxP) and Mrpp3 knockout mice (Mrpp3loxP/loxP, +/Ckmm), TruSeq libraries produced in triplicate, sequenced and analysed for differential expression. Mitochondrial RNA was isolated from heart tissue from 11 week old control (Mrpp3loxP/loxP) and Mrpp3 knockout mice (Mrpp3loxP/loxP, +/Ckmm), PARE libraries produced in triplicate and sequenced for analysis of mitochondrial RNA processing.
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