Epigenetic Changes and Chromatin Reorganization in Brain Function: Lessons from Fear Memory Ensemble and Alzheimer’s Disease

Abstract

Healthy brain functioning in mammals requires a continuous fine-tuning of gene expression. Accumulating evidence over the last three decades demonstrates that epigenetic mechanisms and dynamic changes in chromatin organization are critical components during the control of gene transcription in neural cells. Recent genome-wide analyses show that the regulation of brain genes requires the contribution of both promoter and long-distance enhancer elements, which must functionally interact with upregulated gene expression in response to physiological cues. Hence, a deep comprehension of the mechanisms mediating these enhancer–promoter interactions (EPIs) is critical if we are to understand the processes associated with learning, memory and recall. Moreover, the onset and progression of several neurodegenerative diseases and neurological alterations are found to be strongly associated with changes in the components that support and/or modulate the dynamics of these EPIs. Here, we overview relevant discoveries in the field supporting the role of the chromatin organization and of specific epigenetic mechanisms during the control of gene transcription in neural cells from healthy mice subjected to the fear conditioning paradigm, a relevant model to study memory ensemble. Additionally, special consideration is dedicated to revising recent results generated by investigators working with animal models and human postmortem brain tissue to address how changes in the epigenome and chromatin architecture contribute to transcriptional dysregulation in Alzheimer’s disease, a widely studied neurodegenerative disease. We also discuss recent developments of potential new therapeutic strategies involving epigenetic editing and small chromatin-modifying molecules (or epidrugs).

Bromodomain and Extra-Terminal Proteins in Brain Physiology and Pathology: BET-ing on Epigenetic Regulation

“…Healthy brain functioning requires fine control of gene expression in neural cells. Epigenetic regulatory mechanisms and chromatin remodeling are also crucial for cognitive functions such as learning and memory, which involve specific gene expression profiles that are necessary to ensure neural connectivity and plasticity [ 85 , 86 ].…”

Exploring the Genetic Predisposition to Epigenetic Changes in Alzheimer’s Disease

“…Emerging studies have shown that the multilayered profiles of epigenetic dysregulation, such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation, are intimately involved in various complex disease pathogenesis [92][93][94][95], including neurological diseases [31,[96][97][98]. It is known that along with the impact of environmental factors, genetic pre-disposition plays an important role in the epigenetic changes associated with various pathologies [39,46].…”

Mechanisms of abnormal adult hippocampal neurogenesis in Alzheimer’s disease

“…As technology improves, more and more studies show that epigenetic mechanisms, such as DNA methylation, histone post-translational modifications and microRNA-mediated post-transcriptional gene regulation, are involved in the pathogenesis of AD and thus influence the onset and progression of AD ( Hernaiz et al, 2022 ; van Zundert and Montecino, 2022 ).…”