3 years ago

A complex genomic locus drives mtDNA replicase POLG expression to its disease-related nervous system regions

A complex genomic locus drives mtDNA replicase POLG expression to its disease-related nervous system regions
Maarja Haugas, Anders Paetau, Juha Partanen, Joni Nikkanen, Anu Suomalainen, Diego Balboa, Virginia Brilhante, Juan Cruz Landoni, Pirjo Isohanni
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. Mitochondrial DNA maintenance defects associated with POLG dysfunction manifest with neurological symptoms. Three enhancer elements were here identified to drive POLG expression in the central nervous system regions that degenerate in POLG patients.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/emmm.201707993

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