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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Function of aberrant DNA methylation in shaping neuronal genome during neurodevelopment

Alternative title: Funksjon til avvikende DNA-metylering i utformingen av genom under nevroutvikling

Awarded: NOK 9.6 mill.

Neurodevelopment is a spatially and temporally coordinated process dependent on tightly regulated gene expression. The changes in gene expression are important for generation of functional neurons and of brain as whole. Besides epigenetic DNA modifications that impact gene expression, in each neuron of our brain several thousands of aberrantly methylated DNA bases are generated every day. Our recent work suggests that aberrantly methylated bases, together with enzymes that repair them, accumulate in defined regions of neurodevelopmental genes. In addition, active DNA repair was indicated to characterize healthy neurons and to occur in regions of the genome relevant for neuronal development and function. Despite the links between neuronal health and DNA repair, our knowledge is still surprisingly limited about neuronal genome dynamics and strategies evolved to ensure neuronal distinct longevity. In this project, I aim to determine the function of aberrant DNA methylation in shaping of the neuronal genome. The long-term goal of this study is to reveal new layers in neuronal genome dynamics, with direct implications for brain development and health.

In each neuron of our brain several thousands of aberrantly methylated DNA bases are generated every day. Alkyladenine DNA glycosylase (AAG) is a key enzyme for removal of aberrantly methylated bases and subsequent initiation of base excision repair (BER). DNA repair in neurons occurs primarily in actively transcribed genes. Global increase in aberrant DNA bases is associated with decline in neuronal function and age-specific changes in gene expression. Unexpectedly, active DNA repair occurring in defined regions of the genome, relevant for neuronal development and function, has recently been indicated as an important characteristic of healthy neurons. Consistent with this, our recent work and preliminary findings suggest that aberrantly methylated bases accumulate in defined regions of the genome and have functional roles. Importantly, accumulation of aberrantly methylated bases alters status of epigenetic DNA marks and histone modifications in defined regulatory elements. Co-occurrence of aberrantly methylated and epigenetic DNA bases has potential to alter binding of specific transcription factors, as well as activity of enzymes important for chromatin maintenance. Inability to repair aberrantly methylated bases and their consequent accumulation perturb expression of neurodevelopmental genes. Despite the links between neuronal health and DNA repair, our knowledge is still surprisingly limited about neuronal genome dynamics, precise distribution of aberrantly methylated bases, and strategies evolved to ensure neuronal distinct longevity. In this project, I aim to determine the function of aberrant and epigenetic DNA methylation in shaping of the neuronal genome and ensuring regulated gene expression. Identification of the new concept in regulation of gene expression dependent on the information from aberrant and epigenetic DNA bases, will reveal new layers in neuronal genome dynamics, with direct implications for brain development and health.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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