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

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http://hdl.handle.net/10138/231842

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Nikkanen , J , Landoni , J C , Balboa , D , Haugas , M , Partanen , J , Paetau , A , Isohanni , P , Brilhante , V & Suomalainen , A 2018 , ' A complex genomic locus drives mtDNA replicase POLG expression to its disease-related nervous system regions ' , EMBO molecular medicine , vol. 10 , no. 1 , pp. 13-21 . https://doi.org/10.15252/emmm.201707993

Title: A complex genomic locus drives mtDNA replicase POLG expression to its disease-related nervous system regions
Author: Nikkanen, Joni; Landoni, Juan Cruz; Balboa, Diego; Haugas, Maarja; Partanen, Juha; Paetau, Anders; Isohanni, Pirjo; Brilhante, Virginia; Suomalainen, Anu
Contributor: University of Helsinki, Research Programme for Molecular Neurology
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Research Programs Unit
University of Helsinki, Biosciences
University of Helsinki, Biosciences
University of Helsinki, HUSLAB
University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
Date: 2018-01
Language: eng
Number of pages: 9
Belongs to series: EMBO molecular medicine
ISSN: 1757-4676
URI: http://hdl.handle.net/10138/231842
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.
Subject: enhancer
gene regulation
mtDNA maintenance
POLG
tissue specificity
MITOCHONDRIAL-DNA POLYMERASE
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA
GAMMA MUTATIONS
RECESSIVE ATAXIA
LANDSCAPE
CHROMATIN
BRAIN
CELLS
MICE
3112 Neurosciences
3124 Neurology and psychiatry
3111 Biomedicine
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