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Zundert, B.V.;  Montecino, M. Epigenetic Changes and Chromatin Reorganization in Brain Function. Encyclopedia. Available online: (accessed on 20 May 2024).
Zundert BV,  Montecino M. Epigenetic Changes and Chromatin Reorganization in Brain Function. Encyclopedia. Available at: Accessed May 20, 2024.
Zundert, Brigitte Van, Martin Montecino. "Epigenetic Changes and Chromatin Reorganization in Brain Function" Encyclopedia, (accessed May 20, 2024).
Zundert, B.V., & Montecino, M. (2022, October 27). Epigenetic Changes and Chromatin Reorganization in Brain Function. In Encyclopedia.
Zundert, Brigitte Van and Martin Montecino. "Epigenetic Changes and Chromatin Reorganization in Brain Function." Encyclopedia. Web. 27 October, 2022.
Epigenetic Changes and Chromatin Reorganization in Brain Function

Healthy brain functioning in mammals requires a continuous fine-tuning of gene expression. Accumulating evidence over the past demonstrates that epigenetic mechanisms and dynamic changes in chromatin organization are critical components during the control of gene transcription in neural cells. 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 to upregulate gene expression in response to physiological cues. Hence, a deep comprehension of the mechanisms mediating these enhancer–promoter interactions (EPIs) is critical if people 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. 

epigenetic regulation in brain chromatin organization during cognition mechanisms of synaptic plasticity

1. Introduction

Brain function in mammals requires tight control of gene expression in all neural cells. Moreover, processes mediating learning and memory involve the establishment of cell engrams that support efficient neuron connectivity, which is strongly based on the ability of these cells to express proper gene profiles. Accumulating evidence during the last four decades demonstrates that epigenetic mechanisms modulating dynamic changes in chromatin organization are critical components during the regulation of gene transcription in response to physiological cues (for reviews see [1][2]). Moreover, aberrant epigenetic mechanisms are associated with pathological brain processes, including neurodegenerative disorders such as Alzheimer’s disease (AD) (for reviews see [1][3]). Recent genome-wide studies using postmortem non-diseased human brains also support the intriguing possibility that AD risk variants located in enhancer regions may change gene expression by altering the interaction between promoters and enhancers [4][5]. Together, these findings support the raising concept that the onset and/or progression of several brain-related pathologies may be directly associated with a reduced ability of neural cells to establish and sustain a chromatin configuration that efficiently permits the required gene expression profile. More importantly, the data point to a number of genes and regulatory pathways in brain cells that may be used as potential new therapeutic targets and diagnostic tools.

2. Epigenetic Alterations in Gene Loci Associated with AD Pathogenesis

To understand genetic and non-genetic associations with the onset and progression of AD, a number of researchers have analyzed, over the last two decades, the genomes of twins that are discordant for AD. One large study (11,884 twins, including 392 twin pairs in which 1 or both members had AD) indicated that ~42% of the AD patients lacked heritability [6]. In addition, immunostaining assays against the DNA methylation marker 5-methylcytosine in postmortem brain tissues from a rare pair of monozygotic twins discordant for AD demonstrated that cortical neurons, astrocytes and microglia displayed strongly reduced DNA methylation in the AD twin relative to the neurologically normal, non-demented twin [7]. The fact that the AD twin had extensive contact with pesticides in his work, strongly suggested that these epigenetic changes may have occurred in response to environmental effects. Recent reports also show that air pollution-exposed healthy urbanites (20–40 years old) and mice display reduced enrichment of repressive epigenetic marks (H3K9me2/3) along with hyperphosphorylated tau and amyloid-β plaques [8]. Hence, evidence is emerging that negative environmental factors—including environmental pollutants, infectious agents, diet and psychosocial elements—can impair brain chromatin and increase the risk of developing AD in young individuals [9][10][11].
It has been also important to determine that there is a correlation between the DNA methylation profile and the Braak stages (after correcting for age and gender), where the APP gene promoter is progressively hypomethylated during later stages of AD [14]. These data suggest that progressive loss of DNA methylation at the APP gene promoter, and hence, an epigenetically mediated activation of the APP gene, plays a critical role in driving late-onset AD. Previous methylome profiling studies, however, on purified neural cell populations [14] as well as in hundreds of bulk brain tissue samples [18][19][20] of AD patients, did not bring conclusive evidence to support epigenetic dysregulation in the gene body and/or the promoter regions of other key AD genes involved in the formation of neurofibrillary tangles (GSK3B, MAPT) and regulating the production of Aβ peptide (BACE1, PSEN1, PSEN2). Intriguingly, these studies concluded that changes in DNA methylation are occurring at genes associated with other important processes including inflammation, neurotransmitter homeostasis and transport (e.g., MCF2L, ANK1, HOX3A, MAP2, LRRC8B, STK32C, S100B, KIF26A) [14][20]. Some of these changes in DNA methylation have been found to be restricted to either neurons (i.e., HOX3A) or glia (i.e., ANK1), underscoring the complex interplay between a neuronal versus glial epigenetic burden in the AD brain. Future careful examination of the relationship between DNA methylation and gene expression level in AD-related samples will continue to be necessary as several controversial results remain unclarified in the field (e.g., [21][22]).
Studies focusing on HPTMs also support the role of an aberrant epigenetic regulation in AD. Thus, a recent comprehensive multi-omics analysis—integrating transcriptomic, proteomic and epigenomic analyses of postmortem human brains from AD patients (and comparing to brains of old and young control subjects)—revealed global gains in the active marks H3K27ac and H3K9ac [23]. Moreover, by correlating ChIP-seq and RNA-seq analyses the researchers further showed that these marks are associated with transcription-, chromatin- and disease-related pathways [23].
Using the CK-p25 mouse model (overexpressing p25 (a truncated version of p35) that aberrantly activates cyclin-dependent kinase 5 (Cdk5)), compelling studies by the Tsai laboratory have provided mechanistic insights about the epigenetic dysregulation of histone acetylation that contributes to impaired synaptic plasticity, neurodegeneration and cognitive decline in AD [24][25][26][27][28][29]. In both AD patients and AD mouse models, aberrant synaptic plasticity is associated with a reduction in the expression of genes (mRNA and protein) implicated in learning and memory and synaptic plasticity. This reduced transcription is accompanied by several local epigenetic changes at the promoters of these genes, for example, due to diminished epigenetic activation by CBP/P300 HATs or due to an epigenetic gene suppression mediated by promoter-bound HDACs. Thus, immunostaining assays revealed increased global nuclear levels of HDAC2 in neurons of brain samples from postmortem human sporadic AD patients and several AD mouse models, including CK-p25, 5xFAD (expressing human APP and PSEN1 transgenes with a total of five AD-linked mutations) [26] and AβPPswe/PS-1 (also termed APP/PSEN1, expressing a chimeric mutant mouse/human APP and a mutant human PS1) [30]. As HDAC2 has been shown to interact with the promoter region of many genes involved in memory and synaptic plasticity (Arc, Bdnf, GluR1, NR2A, CaMKII, PSD-95) [25], it was also determined if HDAC2 enrichment is significantly higher at these gene promoters in CK-p25 mice brain [26]. ChIP assays showed increased binding of HDAC2 to genes with critical roles in learning and memory (i.e., Arc, Bdnf) and synaptic plasticity (i.e., GluR1, GluR2, NR2A and NR2B). These studies also confirmed that decreased levels of active histone acetylation marks (e.g., H3K14ac, H4K12ac) accompanied this reduced gene expression profile in CK-p25 mice. These results suggest that in AD, HDAC2 (and likely other HDAC family members) is capable of erasing histone acetylation at these actively transcribed genes. Since histone acetylation-mediated epigenetic control is highly dynamic, it was also determined that a knock-down of HDAC2 [26] or treatment with diverse HDAC inhibitors targeting HDAC2 [24][27][28] rescues pathologic cognitive deficits in AD mice, promoting neuroplasticity-related gene expression, reinstating morphological alterations and synaptic plasticity and restoring memory deficits. Together, these results indicate that transcriptional repression of neuroplasticity genes associated with decreased histone H3 and H4 acetylation may significantly contribute to AD pathology and cognitive impairment.
These results have strongly advocated for the development of effective therapeutic strategies using selective HDAC2 (or to other HDACs) inhibitors that restore an active promoter epigenetic state (H3/H4 acetylation) of critical neuroplasticity genes. Thus, several studies have shown the beneficial effects of a wide variety of HDAC (i.e., HDAC1, HDAC4 and HDAC6) inhibitors on learning and memory, by not only reactivating plasticity but also by modulating Tau function and oxidative DNA repair in AD [27][28][31][32][33][34]. Moreover, during the last decade, small chromatin-modifying molecules, known as epidrugs, have been generated. Recent studies include epigenetic screens of selective small molecule libraries seeking to identify molecules that modulate the activity of histone-modifying enzymes, or alternatively, that can target critical domains (e.g., bromodomains and chromodomains) present in epigenetic readers [35]. These screens have been carried out in experimental models of frontotemporal dementia (FTD) (i.e., expressing hexanucleotide repeat expansion in the C9ORF72 gene), the second most common dementia after AD [36] that exhibit alterations in the repressive marks H3K9me3, H3K9me27 and DNA methylation in neurons and astrocytes [37][38][39][40]. In some of these studies, treatment with a specific class of epidrugs (i.e., JQ1 and PFI-1, both members of the bromodomain and extra-terminal domain (BET) inhibitor family) was shown to restore gene transcription in mouse and human iPSC-derived neurons, and moreover, to ameliorate cognitive deficits in FTD mice [41][42]. However, in a comparable JQ1 treatment it was shown that this BET inhibitor can inhibit non-spatial learning in wild-type mice [43], indicating that additional studies that precisely determine the genomic regions affected by JQ1 treatment are required.
Epigenetic gene regulation can also be mediated by histone methylation. Thus, several studies have focused on the role of the repressive marks H3K9me2 and H3K9me3 that significantly contribute to regulating euchromatin and heterochromatin formation and maintenance in the nucleus. Enrichment of H3K9me2 and H3K9me3 can result in the repression of gene transcription in both euchromatic and facultative heterochromatic regions. These marks can also contribute to maintaining genome stability (by silencing repetitive DNA elements and transposons) and protecting DNA from damage [50][51][52][53][54]. Recent studies have documented altered H3K9me2 and H3K9me3 levels in the brains of patients and experimental models of AD. Intriguingly, in some studies, H3K9me2/3 expression in the nuclei was found to decrease [55][56], whereas in other studies these modifications were shown to be increased [57][58]. Several reasons may explain these seemingly opposite results, including differences in human and mouse brain regions and in the cell types that were examined. In addition, there appear to be significant differences in the methods used for human (postmortem) sample preparation and in the approaches followed to detect H3K9me2. Finally, it is also important to consider that in most cases only limited information (if any information at all) is available about these AD patients, including their genetic background, clinical development, and the presence of specific pathological hallmarks. Together, these uncertainties increase the difficulty of precisely comparing the different analyses carried out in the field and generating strong conclusions from the results.
A recent study [58] reports elevated H3K9me2 levels in the prefrontal cortex of postmortem human AD patient samples (H3K9me2 detected by western blot) and of 5xFAD mice (H3K9me2 detected by western blot and immunostaining). Moreover, ChIP assays on 5xFAD brain samples further confirmed that an increased enrichment of H3K9me2 occurs at the promoters of genes coding for AMPAR (GluR2/GluA2) and NMDAR (NR2B/GluN2B) subunits, concomitantly with decreased expression (detected at mRNA and protein levels) and function of these receptors (measured by electrophysiology). Additionally, it was found that the H3K9 di-methyltransferase EHMT1 (or G9a-like protein, GLP) is upregulated in the prefrontal cortex of the 5xFAD mice. Notably, treatment with the EHMT1/2 (G9a/GLP) inhibitor BIX01294 restored transcription, protein expression and function of AMPARs and NMDARs, and importantly, rescued memory deficits in this AD mouse model [58]. These findings indicate that an EHMT1-mediated increase in histone H3K9 methylation can significantly contribute to transcriptional repression of critical neuroplasticity genes, and hence, to the pathology and cognitive decline in AD. The study also suggests that treatment with specific epidrugs may function as an effective therapeutic strategy to ameliorate, and potentially reverse, memory decline in AD. This conclusion is supported by a parallel study where treatment with the EHMT1/2 inhibitor UNC0642 was capable of restoring cognition parameters in animal models, together with reducing the expression of inflammatory markers and increasing the levels of neurotrophic factors [59].
In another study, Feany and collaborators [55], analyzing FACS-purified neurons of hippocampal tissue obtained from AD patients, also detected a strong reduction of global H3K9me2 levels. Interestingly, they found that the expression of euchromatic genes remained largely unchanged between brain samples from control and AD subjects. Moreover, it was determined that this depletion of H3K9me2 in AD affects the expression of genes that are mostly located at genomic regions silenced by heterochromatin in normal hippocampal cells. Notably, widespread transcriptional increases in non-coding genes (including piwi transcripts; see below) that are normally silenced in controls, were detected in AD patient brain samples. This heterochromatin loss and aberrant gene expression were found to be conserved among mouse and Drosophila tauopathy models [55]. Thus, ChIP-seq assays in tau transgenic flies revealed a strong loss of H3K9me2 enrichment at genes like Ago3 (which is homologous to the human gene PIWIL1), concomitant with upregulated gene transcription. In a posterior study, Frost and colleagues [60] demonstrated that de-condensation of constitutive heterochromatin occurs concomitant with transcriptional activation of transposable elements in the brains of postmortem human AD patient samples as well as in brain cells of fly models. Mechanistically, the researchers proposed an interesting model where tau-induced heterochromatin de-condensation facilitates active transcription of transposable elements and that tau-induced depletion of piwi and piwi-interacting RNAs (piRNAs) enables the transcripts from the transposable elements to remain elevated. How a pathologic tau precisely causes a global loss of heterochromatin-dependent silencing is still not understood. A strong role of DNA damage, induced by excessive oxidative stress, has been postulated [55][61]. Similarly, it has been proposed that the loss of the physiological role of endogenous tau, which directly binds and regulates H3K9me3-rich pericentromeric heterochromatin integrity in neurons, is an important component [56][62].

3. Epigenetic Changes Impact Promoter–Enhancer Interactions in AD

As discussed above, the vast majority of AD cases cannot be explained by pathogenic mutations occurring in AD protein-coding genes. In the last 10 years, next-generation sequencing (NGS) and genome-wide association studies (GWAS) have led to the identification of numerous low penetrance predisposing genetic mutations and single nucleotide polymorphisms (SNPs) at more than 40 susceptibility loci associated with late-onset AD [63][64][65]. Identification of AD-associated variants in a specific-coding gene has only been established for a few loci (e.g., APP, TREM2, TREML2, PLCG2, UNC5C, ADAM10, AKAP9). Intriguingly, cell type-specific gene expression profiling and analysis of related biological processes show that several of these genetic variants are selectively expressed in microglia and involved in immune responses and lipid metabolism (e.g., TREM2, TREML2, PLCG2) [64][66].
In the past few years, comprehensive genome- and epigenome-wide maps have been created to find that many AD susceptibility loci lie in putative cell-type-specific enhancer elements. Initial support to this novel concept came from a study comparing transcriptional and chromatin states between hippocampal samples from the AD-like mouse model CK-p25 and humans, followed by a close examination of the enrichment of AD-related SNPs within conserved enhancers [29]. Briefly, transcription and chromatin dynamics (measured by ChIP-seq to identify putative primed/active promoters and enhancers; see above) were examined across early (2 weeks) and late (6 weeks after p25 induction) stages of pathology in CK-p25 mice. In agreement with previous studies, it was determined that during the late stages of AD pathology genes involved in synaptic plasticity and learning were down-regulated, concurrent with reductions in the activity of their assigned promoter and enhancer regions [26]. In contrast, during the early stages of AD pathology, immune-response genes were found upregulated, concomitant with increases in the activity of their cognate-regulatory genomic regions. Researchers then mapped orthologous coding and non-coding regions between mouse and human hippocampal samples, identifying significant human-to-mouse conservation of epigenomic signatures and gene expression profiles. Notable was the result indicating that AD-associated genetic variants (i.e., PICALM, BIN1, NPP5D, CELF1/SPI1, PTK2B) were specifically enriched at enhancer orthologues that displayed increased activity, implicating a role of immune-related processes in AD predisposition [29]. These results in the CK-p25 mice also indicated that epigenetic changes (without SNPs) in regulatory regions controlling immune processes and synaptic plasticity can contribute to AD pathology.
In two recent studies, using postmortem non-diseased human brains, chromatin interactions between enhancers and promoters were established by subjecting specific cell-type populations to pc-HiC analysis [5], in combination with ATAC-seq and PLAC-seq (proximity ligation-assisted ChIP that captures EPIs with active H3K4me3 bearing promoters) [4]. Epigenomic annotations were used to identify putative primed/active promoters and enhancers (as described above). As expected, chromatin loops were detected between active promoters and distal regulatory regions in neurons, microglia, astrocytes and oligodendrocytes [4][5]. By examining the genomic location of disease-associated GWAS variants, it was determined that AD variants were only enriched in microglia enhancers (i.e., BIN1, PICALM, SORL1, SPI1). This is a particularly intriguing result as most polymorphisms associated with psychiatric and neurological disorders (e.g., autism, schizophrenia, neuroticism) have been located in neuronal enhancers and promoters, with few of the SNPs located in glial promoters. Integration of the genome-wide studies further indicated that BIN1 is a microglia-specific enhancer as it interacts with the BIN1 promoter and is specifically detected in microglia cells but not in neurons, astrocytes or oligodendrocytes [4]. Importantly, this BIN1 microglia-specific enhancer also harbors the AD risk variant rs6733839, which has the second highest AD-risk score after APOE. To determine whether this microglia-specific enhancer is functional, a CRISPR/Cas9-mediated deletion of a 363-bp region harboring rs6733839 in human iPSC lines was performed, and these cells were then differentiated to microglia, astrocytes and neurons. Interestingly, the edition of this regulatory region leads to a microglia-specific reduction in BIN1 mRNA and protein expression [4]. Although the study did not demonstrate the functionality of the specific SNP (e.g., editing by CRISPR), the data support the intriguing possibility that AD risk variants located in enhancer regions could change gene expression by altering the interaction between enhancer-promoter.


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