A complex genomic locus drives mtDNA replicase POLG expression to its disease‐related nervous system regions
Abstract DNA polymerase gamma (POLG), the mtDNA replicase, is a common cause of mitochondrial neurodegeneration. Why POLG defects especially cause central nervous system (CNS) diseases is unknown. We discovered a complex genomic regulatory locus for POLG, containing three functional CNS‐specific enh...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-01-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201707993 |
| _version_ | 1797285668245733376 |
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| author | Joni Nikkanen Juan Cruz Landoni Diego Balboa Maarja Haugas Juha Partanen Anders Paetau Pirjo Isohanni Virginia Brilhante Anu Suomalainen |
| author_facet | Joni Nikkanen Juan Cruz Landoni Diego Balboa Maarja Haugas Juha Partanen Anders Paetau Pirjo Isohanni Virginia Brilhante Anu Suomalainen |
| author_sort | Joni Nikkanen |
| collection | DOAJ |
| description | Abstract DNA polymerase gamma (POLG), the mtDNA replicase, is a common cause of mitochondrial neurodegeneration. Why POLG defects especially cause central nervous system (CNS) diseases is unknown. We discovered a complex genomic regulatory locus for POLG, containing three functional CNS‐specific enhancers that drive expression specifically in oculomotor complex and sensory interneurons of the spinal cord, completely overlapping with the regions showing neuronal death in POLG patients. The regulatory locus also expresses two functional RNAs, LINC00925‐RNA and MIR9‐3, which are coexpressed with POLG. The MIR9‐3 targets include NR2E1, a transcription factor maintaining neural stem cells in undifferentiated state, and MTHFD2, the regulatory enzyme of mitochondrial folate cycle, linking POLG expression to stem cell differentiation and folate metabolism. Our evidence suggests that distant genomic non‐coding regions contribute to regulation of genes encoding mitochondrial proteins. Such genomic arrangement of POLG locus, driving expression to CNS regions affected in POLG patients, presents a potential mechanism for CNS‐specific manifestations in POLG disease. |
| first_indexed | 2024-03-07T18:06:28Z |
| format | Article |
| id | doaj.art-6fb47723ca3249a4bdd9968545195a44 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:06:28Z |
| publishDate | 2018-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-6fb47723ca3249a4bdd9968545195a442024-03-02T09:04:13ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-01-01101132110.15252/emmm.201707993A complex genomic locus drives mtDNA replicase POLG expression to its disease‐related nervous system regionsJoni Nikkanen0Juan Cruz Landoni1Diego Balboa2Maarja Haugas3Juha Partanen4Anders Paetau5Pirjo Isohanni6Virginia Brilhante7Anu Suomalainen8Research Programs Unit Molecular Neurology University of Helsinki Helsinki FinlandResearch Programs Unit Molecular Neurology University of Helsinki Helsinki FinlandResearch Programs Unit Molecular Neurology University of Helsinki Helsinki FinlandDepartment of Biosciences University of Helsinki Helsinki FinlandDepartment of Biosciences University of Helsinki Helsinki FinlandHUSLAB and Department of Pathology University of Helsinki and Helsinki University Hospital Helsinki FinlandResearch Programs Unit Molecular Neurology University of Helsinki Helsinki FinlandResearch Programs Unit Molecular Neurology University of Helsinki Helsinki FinlandResearch Programs Unit Molecular Neurology University of Helsinki Helsinki FinlandAbstract DNA polymerase gamma (POLG), the mtDNA replicase, is a common cause of mitochondrial neurodegeneration. Why POLG defects especially cause central nervous system (CNS) diseases is unknown. We discovered a complex genomic regulatory locus for POLG, containing three functional CNS‐specific enhancers that drive expression specifically in oculomotor complex and sensory interneurons of the spinal cord, completely overlapping with the regions showing neuronal death in POLG patients. The regulatory locus also expresses two functional RNAs, LINC00925‐RNA and MIR9‐3, which are coexpressed with POLG. The MIR9‐3 targets include NR2E1, a transcription factor maintaining neural stem cells in undifferentiated state, and MTHFD2, the regulatory enzyme of mitochondrial folate cycle, linking POLG expression to stem cell differentiation and folate metabolism. Our evidence suggests that distant genomic non‐coding regions contribute to regulation of genes encoding mitochondrial proteins. Such genomic arrangement of POLG locus, driving expression to CNS regions affected in POLG patients, presents a potential mechanism for CNS‐specific manifestations in POLG disease.https://doi.org/10.15252/emmm.201707993enhancergene regulationmtDNA maintenancePOLGtissue specificity |
| spellingShingle | Joni Nikkanen Juan Cruz Landoni Diego Balboa Maarja Haugas Juha Partanen Anders Paetau Pirjo Isohanni Virginia Brilhante Anu Suomalainen A complex genomic locus drives mtDNA replicase POLG expression to its disease‐related nervous system regions EMBO Molecular Medicine enhancer gene regulation mtDNA maintenance POLG tissue specificity |
| title | A complex genomic locus drives mtDNA replicase POLG expression to its disease‐related nervous system regions |
| title_full | A complex genomic locus drives mtDNA replicase POLG expression to its disease‐related nervous system regions |
| title_fullStr | A complex genomic locus drives mtDNA replicase POLG expression to its disease‐related nervous system regions |
| title_full_unstemmed | A complex genomic locus drives mtDNA replicase POLG expression to its disease‐related nervous system regions |
| title_short | A complex genomic locus drives mtDNA replicase POLG expression to its disease‐related nervous system regions |
| title_sort | complex genomic locus drives mtdna replicase polg expression to its disease related nervous system regions |
| topic | enhancer gene regulation mtDNA maintenance POLG tissue specificity |
| url | https://doi.org/10.15252/emmm.201707993 |
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