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

Joni Nikkanen,Virginia Brilhante,Anders Paetau,Diego Balboa,Maarja Haugas,Anu Suomalainen,Pirjo Isohanni,Juan Cruz Landoni,Juha Partanen

doi:10.15252/emmm.201707993

Joni Nikkanen, Virginia Brilhante + Show 7 more

Open Access

https://doi.org/10.15252/emmm.201707993

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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.

Highlights

Mutations in the genes encoding mitochondrial DNA replisome proteins cause mtDNA maintenance defects, which lead to common metabolic disorders (Viscomi & Zeviani, 2017)
To clarify the upstream regulation of the mtDNA replicase expression, we analyzed the activity of the proximal promoter of polymerase gamma (POLG)
In transgenic E12.5 mouse embryos, the Polg promoter was active especially in the midbrain, dorsal root ganglia (DRG), developing motoneurons of the neural tube, and in skeletal muscle somites with very low expression outside central nervous system (CNS) (Fig 1C). This muscle–CNS expression pattern was surprising for a mtDNA replicase, because of ubiquitous requirement of the mitochondrial genome replication, and raised the question whether the tissue-specific expression pattern of the proximal Polg promoter was modified by potential enhancer elements (EEs)

Summary

Introduction

Mutations in the genes encoding mitochondrial DNA (mtDNA) replisome proteins cause mtDNA maintenance defects, which lead to common metabolic disorders (Viscomi & Zeviani, 2017). Despite the apparent requirement of mtDNA replication in cell division, the patients with POLG disorders do not typically show symptoms deriving from highly proliferating cell types, such as anemia. The reasons for such postmitotic cell manifestations—and mechanisms of tissue specificity overall—are unknown. The variability of CNS manifestations even in patients with the same disease allele indicates strong modifier effects/genes contributing to the manifestations. These observations prompted us to explore the genomic regions of mtDNA maintenance loci to identify potential genomic modifiers for these disorders

Results and Discussion

E Conservation of regulatory elements of POLG genomic locus in species

Materials and Methods

Results

Conflict of interest