The Transcriptome and Methylome of the Developing and Aging Brain and Their Relations to Gliomas and Psychological Disorders.

Henry Loeffler-Wirth,Lydia Hopp,Roksana Zakharyan,Hans Binder,Arsen Arakelyan,Maria Schmidt

doi:10.3390/cells11030362

Abstract

Mutually linked expression and methylation dynamics in the brain govern genome regulation over the whole lifetime with an impact on cognition, psychological disorders, and cancer. We performed a joint study of gene expression and DNA methylation of brain tissue originating from the human prefrontal cortex of individuals across the lifespan to describe changes in cellular programs and their regulation by epigenetic mechanisms. The analysis considers previous knowledge in terms of functional gene signatures and chromatin states derived from independent studies, aging profiles of a battery of chromatin modifying enzymes, and data of gliomas and neuropsychological disorders for a holistic view on the development and aging of the brain. Expression and methylation changes from babies to elderly adults decompose into different modes associated with the serial activation of (brain) developmental, learning, metabolic and inflammatory functions, where methylation in gene promoters mostly represses transcription. Expression of genes encoding methylome modifying enzymes is very diverse reflecting complex regulations during lifetime which also associates with the marked remodeling of chromatin between permissive and restrictive states. Data of brain cancer and psychotic disorders reveal footprints of pathophysiologies related to brain development and aging. Comparison of aging brains with gliomas supports the view that glioblastoma-like and astrocytoma-like tumors exhibit higher cellular plasticity activated in the developing healthy brain while oligodendrogliomas have a more stable differentiation hierarchy more resembling the aged brain. The balance and specific shifts between volatile and stable and between more irreversible and more plastic epigenomic networks govern the development and aging of healthy and diseased brain.

Highlights

The human brain relies on the lifelong function of its diverse neuronal cell types
Molecular shaping during prenatal development via DNA methylation, histone modifications, and other molecular constituents of the epigenome are likely to play a critical role in the maintenance of neuronal health and function throughout the entire lifespan [6]
We aimed to identify the functional context of the modes and their relation to epigenetic mechanisms such as the expression of genes encoding chromatinmodifying enzymes and of genes located in different chromatin states [23,24]

Summary

Introduction

The human brain relies on the lifelong function of its diverse neuronal cell types. Most neurons emerge during development in the fetal and baby’s brain and need to be maintained throughout adulthood. Neuronal health is governed by cellular programs, which need to be flexible to mediate neuronal plasticity, and yet stable to express a constant set of cell-type-specific genes throughout the life of the neurons [1]. Epigenetic, changes including DNA methylation, histone modifications, and chromatin remodeling, profoundly affect cellular function, thereby contributing to the progression of aging and to age-related declines in cognition. Molecular shaping during prenatal development via DNA methylation, histone modifications, and other molecular constituents of the epigenome are likely to play a critical role in the maintenance of neuronal health and function throughout the entire lifespan [6]. DNA methylation drifts with age [10] with impact on other epigenetic marks, such as histone modification, in turn affecting chromatin states [11]. Overall, altered DNA methylation is among the central mechanisms in development, aging, and cellular senescence [12]

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