Progressive Supranuclear Palsy (PSP) is a 4R-tauopathy characterized by progressive supranuclear gaze palsy, postural instability, parkinsonism, and cognitive impairment. Epigenetic modifications—heritable changes in gene expression without alterations to the DNA sequence—have emerged as critical contributors to PSP pathogenesis [@dna](https://pubmed.ncbi.nlm.nih.gov/24717639/). These epigenetic changes affect multiple biological processes including tau metabolism, neuronal survival, neuroinflammation, and cellular stress responses.
The study of epigenetics in PSP provides insights into how environmental factors, aging, and genetic susceptibility interact to drive disease progression. Unlike genetic mutations, epigenetic modifications are potentially reversible, making them attractive therapeutic targets. This comprehensive review explores the current understanding of epigenetic alterations in PSP, including DNA methylation patterns, histone modifications, and non-coding RNA-mediated regulation, with particular emphasis on their roles in tau pathology and neurodegeneration [@epigenetic](https://pubmed.ncbi.nlm.nih.gov/30662187/).
Progressive Supranuclear Palsy (PSP) is a 4R-tauopathy characterized by progressive supranuclear gaze palsy, postural instability, parkinsonism, and cognitive impairment. Epigenetic modifications—heritable changes in gene expression without alterations to the DNA sequence—have emerged as critical contributors to PSP pathogenesis [@dna](https://pubmed.ncbi.nlm.nih.gov/24717639/). These epigenetic changes affect multiple biological processes including tau metabolism, neuronal survival, neuroinflammation, and cellular stress responses.
The study of epigenetics in PSP provides insights into how environmental factors, aging, and genetic susceptibility interact to drive disease progression. Unlike genetic mutations, epigenetic modifications are potentially reversible, making them attractive therapeutic targets. This comprehensive review explores the current understanding of epigenetic alterations in PSP, including DNA methylation patterns, histone modifications, and non-coding RNA-mediated regulation, with particular emphasis on their roles in tau pathology and neurodegeneration [@epigenetic](https://pubmed.ncbi.nlm.nih.gov/30662187/).
PSP belongs to the spectrum of frontotemporal lobar degeneration (FTLD) disorders and represents one of the most common atypical parkinsonian syndromes, affecting approximately 5-7 per 100,000 individuals worldwide. The disease is defined neuropathologically by the accumulation of hyperphosphorylated tau protein in neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies, predominantly affecting brainstem nuclei, basal ganglia, and cerebral cortex [@neuropathology](https://pubmed.ncbi.nlm.nih.gov/25717144/).
The advent of genome-wide epigenetic profiling technologies has revolutionized our understanding of PSP pathogenesis. Epigenetic mechanisms provide a crucial interface between environmental exposures and genetic vulnerability, potentially explaining the variable penetrance and phenotypic heterogeneity observed in PSP patients. The aging brain undergoes profound epigenetic remodeling, characterized by global DNA hypomethylation, site-specific hypermethylation, and altered histone modification patterns—changes that may synergize with disease-specific mechanisms to promote neurodegeneration [@dnaa](https://pubmed.ncbi.nlm.nih.gov/29238568/).
DNA methylation involves the covalent addition of a methyl group to cytosine residues in CpG dinucleotides, typically resulting in transcriptional repression when occurring in gene promoter regions. Studies examining global DNA methylation in PSP post-mortem brain tissue have revealed distinctive patterns compared to age-matched controls and other neurodegenerative conditions. Research has demonstrated that PSP brains exhibit region-specific alterations in 5-methylcytosine content, with particularly notable changes in the prefrontal cortex, brainstem, and cerebellum—areas selectively vulnerable to tau pathology [@genomewide](https://pubmed.ncbi.nlm.nih.gov/33300523/).
The methylome of PSP reveals a characteristic " epigenetic signature" that differs from Alzheimer's disease and other tauopathies, suggesting that distinct mechanisms drive tau accumulation in different disorders. These region-specific methylation patterns correlate with the topographical distribution of tau pathology, suggesting a potential mechanistic relationship between epigenetic dysregulation and regional neuronal vulnerability [@epigenetica](https://pubmed.ncbi.nlm.nih.gov/33907953/).
Genome-wide methylation studies have identified numerous differentially methylated regions (DMRs) in PSP brains. Among the most significantly altered genes are those involved in:
Tau metabolism genes: The MAPT gene encoding tau shows altered methylation patterns in PSP, particularly in the promoter region and intron 1, which contains regulatory elements influencing alternative splicing. Hypomethylation of specific CpG sites within the MAPT promoter has been associated with increased tau expression, potentially contributing to the excessive 4R-tau production characteristic of PSP [@mapt](https://pubmed.ncbi.nlm.nih.gov/26574550/).
Neuroprotection genes: Methylation analysis has revealed hypermethylation of genes encoding cellular stress response proteins, including sirtuins (SIRT1, SIRT2) and antioxidant enzymes. The hypermethylation-induced silencing of these protective pathways may render neurons more susceptible to tau-induced toxicity and oxidative stress [@dnab](https://pubmed.ncbi.nlm.nih.gov/28333547/).
Inflammatory genes: Dysregulated methylation of genes involved in microglial activation and neuroinflammation has been documented in PSP. Pro-inflammatory genes such as TNF-α, IL-6, and complement components show altered methylation patterns that may contribute to the chronic neuroinflammatory state observed in PSP brains [@epigeneticb](https://pubmed.ncbi.nlm.nih.gov/30594490/).
Epigenetic regulatory genes: Perhaps most intriguingly, genes encoding DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes exhibit differential methylation in PSP, suggesting the existence of a self-perpetuating epigenetic dysregulation cascade [@dnac](https://pubmed.ncbi.nlm.nih.gov/30104667/).
The enzymes responsible for establishing and maintaining DNA methylation patterns—DNMT1, DNMT3A, and DNMT3B—show altered expression and activity in PSP. DNMT1, the maintenance methyltransferase, demonstrates increased activity in PSP brains, particularly in regions with abundant tau pathology. This elevated DNMT1 activity correlates with the hypermethylation of neuroprotective genes and may represent a maladaptive response to cellular stress [@histone](https://pubmed.ncbi.nlm.nih.gov/29024652/).
Experimental studies have shown that pharmacological inhibition of DNMTs can protect neurons from tau-induced toxicity, suggesting that targeting DNA methylation machinery may have therapeutic potential in PSP and related tauopathies.
Histone acetylation, mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), represents a crucial epigenetic mechanism regulating gene expression through chromatin accessibility. In PSP, alterations in histone acetylation patterns contribute significantly to transcriptional dysregulation observed in affected neurons.
Global histone hypoacetylation: Post-mortem studies have documented reduced acetylation of histone H3 at lysine residues (particularly H3K9, H3K14, and H3K27) in PSP brains. This global hypoacetylation state is associated with transcriptional repression of genes involved in neuronal survival, synaptic function, and cellular homeostasis [@global](https://pubmed.ncbi.nlm.nih.gov/25920527/).
HDAC alterations: The class I histone deacetylases HDAC1, HDAC2, and HDAC3 show increased expression and activity in PSP brains, contributing to the aberrant transcriptional repression. HDAC6, a unique class IIb HDAC with tubulin deacetylase activity, is particularly implicated in PSP pathogenesis. HDAC6 abnormalities affect axonal transport, autophagy, and tau acetylation—a post-translational modification that influences tau aggregation and toxicity [@hdac](https://pubmed.ncbi.nlm.nih.gov/32843761/).
Therapeutic targeting of HDACs: Preclinical studies using pan-HDAC inhibitors (such as sodium valproate and vorinostat) and selective HDAC6 inhibitors have demonstrated neuroprotective effects in cellular and animal models of tauopathy. These compounds reduce tau phosphorylation, enhance autophagy, and improve behavioral outcomes, supporting the therapeutic potential of histone deacetylase modulation in PSP [@hdaca](https://pubmed.ncbi.nlm.nih.gov/28709191/).
Unlike acetylation, histone methylation can be associated with either transcriptional activation or repression depending on the specific residue modified and the extent of methylation (mono-, di-, or trimethylation).
H3K9 methylation: The trimethylation of histone H3 at lysine 9 (H3K9me3), a repressive mark associated with constitutive heterochromatin, is altered in PSP. Studies have shown redistribution of H3K9me3 in affected neurons, with loss from pericentromeric regions and accumulation at gene promoters, contributing to genomic instability and transcriptional dysregulation [@methylation](https://pubmed.ncbi.nlm.nih.gov/26442585/).
H3K27 methylation: Trimethylation of H3K27 (H3K27me3), catalyzed by the Polycomb repressive complex 2 (PRC2), is elevated at specific gene loci in PSP. This aberrant PRC2 activity silences genes essential for neuronal function and survival, including neurotrophic factors and synaptic proteins [@polycomb](https://pubmed.ncbi.nlm.nih.gov/27350244/).
H3K4 methylation: Active histone marks such as H3K4me3 show altered patterns in PSP, particularly at genes involved in stress response pathways. These changes reflect the complex dysregulation of transcriptional programs that characterizes affected neurons [@histonea](https://pubmed.ncbi.nlm.nih.gov/28381393/).
ATP-dependent chromatin remodeling complexes, including SWI/SNF, ISWI, and CHD families, regulate nucleosome positioning to control DNA accessibility. Alterations in these complexes have been implicated in PSP pathogenesis. The BRG1 (SMARCA4) and BRM (SMARCA2) subunits of the SWI/SNF complex show altered expression in PSP brains, affecting the chromatin landscape and contributing to transcriptional dysregulation of genes involved in tau metabolism and neuronal survival [@swisnf](https://pubmed.ncbi.nlm.nih.gov/29967468/).
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally by binding to complementary sequences in target mRNAs, leading to translational repression or mRNA degradation. Dysregulated miRNA expression is a hallmark of PSP and contributes to disease pathogenesis through multiple mechanisms [@noncoding](https://pubmed.ncbi.nlm.nih.gov/26315666/).
miR-124: This neuron-enriched miRNA is significantly downregulated in PSP brains and CSF. miR-124 targets multiple mRNAs involved in tau phosphorylation (including CDK5 and GSK3β regulatory subunits) and its reduction contributes to increased tau pathology. Restoration of miR-124 in experimental models reduces tau phosphorylation and improves neuronal viability [@microrna](https://pubmed.ncbi.nlm.nih.gov/31743697/).
miR-132 family: The miR-132/212 cluster, critical for neuronal development and function, shows altered expression in PSP. These miRNAs regulate genes involved in cytoskeletal dynamics, synaptic plasticity, and autophagy. Their dysregulation contributes to tau pathology, synaptic dysfunction, and impaired neuronal homeostasis [@mir](https://pubmed.ncbi.nlm.nih.gov/29046360/).
miR-219: This brain-specific miRNA is reduced in PSP and targets multiple components of the tau kinase signaling network, including GSK3β and MAPK pathways. Loss of miR-219-mediated restraint on tau kinases may contribute to excessive tau phosphorylation in PSP [@mira](https://pubmed.ncbi.nlm.nih.gov/26945584/).
Inflammatory miRNAs: Several miRNAs regulating neuroinflammation are dysregulated in PSP, including miR-155 (pro-inflammatory) which is upregulated, and miR-146a (anti-inflammatory regulator) which shows complex alterations. These changes reflect and contribute to the chronic neuroinflammatory state characteristic of PSP [@inflammatory](https://pubmed.ncbi.nlm.nih.gov/27756157/).
Long non-coding RNAs (lncRNAs, >200 nucleotides) participate in diverse regulatory functions, including chromatin remodeling, transcriptional regulation, and post-transcriptional processing. Emerging evidence implicates lncRNAs in PSP pathogenesis [@long](https://pubmed.ncbi.nlm.nih.gov/30323220/).
NEAT1: The nuclear-enriched abundant transcript 1 (NEAT1) lncRNA, essential for nuclear speckle formation and RNA processing, is upregulated in PSP brains. NEAT1 sequesters transcription factors and splicing factors, altering gene expression programs that may contribute to tau pathology and neuronal dysfunction [@neat](https://pubmed.ncbi.nlm.nih.gov/31365917/).
MALAT1: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), involved in alternative splicing and synaptic function, shows altered expression in PSP. Changes in MALAT1 levels affect splicing of tau exon 10, potentially influencing the 4R-tau/3R-tau ratio characteristic of PSP [@malat](https://pubmed.ncbi.nlm.nih.gov/30278773/).
Tau antisense transcripts: Natural antisense transcripts (NATs) of the MAPT gene have been identified and shown to regulate tau expression. Altered expression of these antisense RNAs in PSP may contribute to the dysregulated tau metabolism central to disease pathogenesis [@natural](https://pubmed.ncbi.nlm.nih.gov/29106877/).
Epigenetic mechanisms directly influence both the expression and alternative splicing of tau (MAPT) pre-mRNA. The transition from 3R-tau to 4R-tau isoforms that characterizes PSP results largely from alternative splicing of exon 10, regulated by multiple cis-acting elements and trans-acting factors whose expression is epigenetically controlled [@epigeneticc](https://pubmed.ncbi.nlm.nih.gov/25609626/).
Histone modifications at the MAPT locus: Chromatin immunoprecipitation studies have revealed altered histone modification patterns at the MAPT gene locus in PSP. Specific histone marks correlate with the increased inclusion of exon 10, suggesting that epigenetic remodeling of the MAPT chromatin environment contributes to 4R-tau predominance [@histoneb](https://pubmed.ncbi.nlm.nih.gov/24841694/).
DNA methylation of splicing regulators: Genes encoding tau splicing factors, including SFRS1 (ASF/SF2), PTBP2, and RBM3, show altered methylation in PSP. These changes affect the expression and activity of proteins that regulate exon 10 inclusion, propagating the dysregulation of tau isoform expression [@dnad](https://pubmed.ncbi.nlm.nih.gov/27545675/).
Beyond regulating tau expression and splicing, epigenetic mechanisms influence tau post-translational modifications (PTMs) that determine its aggregation propensity and toxicity.
Acetylation: Tau acetylation at lysine residues (particularly K280 and K281) promotes aggregation and impairs degradation. SIRT1, a NAD+-dependent deacetylase, deacetylates tau and promotes its clearance. Reduced SIRT1 expression and activity in PSP, influenced by epigenetic silencing, may contribute to tau acetylation and accumulation [@sirt](https://pubmed.ncbi.nlm.nih.gov/25217766/).
Phosphorylation: The balance between tau kinases (GSK3β, CDK5, MAPK) and phosphatases (PP2A) is epigenetically regulated in PSP. Altered expression of these enzymes due to epigenetic dysregulation shifts the phosphorylation equilibrium toward hyperphosphorylated tau [@epigeneticd](https://pubmed.ncbi.nlm.nih.gov/26442585/).
Methylation: Recent studies have identified lysine methylation of tau as a regulatory PTM. The enzymes mediating tau methylation and demethylation show altered expression in PSP, suggesting epigenetic contributions to this novel regulatory layer [@tau](https://pubmed.ncbi.nlm.nih.gov/28711625/).
While PSP is considered a sporadic disease in the majority of cases, environmental factors may contribute to disease risk and progression. Epigenetic mechanisms provide a plausible biological interface through which environmental exposures influence disease pathogenesis [@environmental](https://pubmed.ncbi.nlm.nih.gov/29580820/).
Heavy metals: Exposure to heavy metals, including iron and manganese, has been proposed as a potential risk factor for PSP. These metals can alter DNA methylation patterns and histone modifications in neurons, affecting genes involved in oxidative stress response, mitochondrial function, and tau metabolism [@heavy](https://pubmed.ncbi.nlm.nih.gov/27524673/).
Pesticides and industrial chemicals: Epidemiological studies have suggested associations between pesticide exposure and parkinsonian disorders. Animal models demonstrate that certain pesticides can induce epigenetic changes similar to those observed in PSP, including altered DNA methylation and histone modification patterns [@pesticides](https://pubmed.ncbi.nlm.nih.gov/28984647/).
Diet and metabolic factors: Caloric restriction and specific dietary components can influence epigenetic landscapes through sirtuin activation and methyl donor metabolism. These findings suggest potential lifestyle interventions that might modify disease risk or progression [@dietary](https://pubmed.ncbi.nlm.nih.gov/28197071/).
The strong association between PSP and aging suggests that age-related epigenetic changes may contribute to disease pathogenesis. The concept of "epigenetic drift" describes the gradual divergence in epigenetic patterns with age, influenced by cumulative environmental exposures, cellular turnover, and systemic changes [@epigenetice](https://pubmed.ncbi.nlm.nih.gov/28940004/).
Epigenetic clocks: DNA methylation-based biomarkers of aging (epigenetic clocks) show accelerated aging in PSP brains. The epigenetic age acceleration observed in PSP correlates with pathological burden and may reflect increased cellular stress and altered stem cell-like programs [@epigeneticf](https://pubmed.ncbi.nlm.nih.gov/29346756/).
Senescence and SASP: Age-related cellular senescence is associated with characteristic epigenetic changes. Senescent neurons and glial cells in PSP brains may adopt a senescence-associated secretory phenotype (SASP), contributing to neuroinflammation and spreading of tau pathology through exosomal release [@cellular](https://pubmed.ncbi.nlm.nih.gov/30341427/).
The identification of disease-specific epigenetic signatures in PSP offers potential for biomarker development, addressing the critical need for sensitive and specific diagnostic markers.
CSF epigenetic markers: Circulating cell-free DNA and RNA in cerebrospinal fluid (CSF) may provide accessible biomarkers for PSP diagnosis and monitoring. Studies have detected disease-specific methylation patterns and miRNA signatures in CSF from PSP patients, although sensitivity and specificity require further validation [@cerebrospinal](https://pubmed.ncbi.nlm.nih.gov/31315246/).
Blood-based epigenetic biomarkers: Peripheral blood mononuclear cells and plasma-derived exosomes contain epigenetic information that may reflect CNS changes. Specific miRNA signatures and DNA methylation patterns in blood have shown promise for distinguishing PSP from other parkinsonian disorders [@bloodbased](https://pubmed.ncbi.nlm.nih.gov/30476485/).
Epigenetic progression markers: Longitudinal studies suggest that certain epigenetic changes may correlate with disease progression, potentially serving as pharmacodynamic biomarkers for therapeutic trials [@epigeneticg](https://pubmed.ncbi.nlm.nih.gov/31504543/).
The reversibility of epigenetic modifications makes them attractive therapeutic targets. Several epigenetic-modifying approaches are under investigation for PSP and related tauopathies [@epigenetich](https://pubmed.ncbi.nlm.nih.gov/30804664/).
HDAC inhibitors: As discussed, HDAC inhibitors can restore histone acetylation, improve transcriptional homeostasis, and reduce tau pathology. However, the pleiotropic effects of pan-HDAC inhibitors necessitate the development of isoform-selective compounds with improved CNS penetration and safety profiles [@hdacb](https://pubmed.ncbi.nlm.nih.gov/28542699/).
DNMT inhibitors: DNA methyltransferase inhibitors (5-azacytidine, decitabine) have shown efficacy in reducing tau phosphorylation and improving neuronal survival in preclinical models. However, the global hypomethylation induced by these agents raises concerns about genomic instability and off-target effects [@dnmt](https://pubmed.ncbi.nlm.nih.gov/28647586/).
miRNA-based therapeutics: Restoration of depleted miRNAs (such as miR-124 and miR-132) using miRNA mimics, or inhibition of upregulated pathogenic miRNAs using antagomirs, represents a targeted therapeutic approach. Viral vector-mediated miRNA delivery has shown promise in animal models of tauopathy [@micrornabased](https://pubmed.ncbi.nlm.nih.gov/30450109/).
BET bromodomain inhibitors: Bromodomain and extra-terminal (BET) proteins read acetyl-lysine marks on histones and participate in transcriptional regulation. BET inhibitors have shown neuroprotective effects in tauopathy models by modulating the expression of inflammatory and pro-apoptotic genes [@bet](https://pubmed.ncbi.nlm.nih.gov/29729019/).
Combination approaches: The multifactorial nature of epigenetic dysregulation in PSP suggests that combination therapies targeting multiple epigenetic mechanisms may be more effective than single-agent approaches. Preclinical studies combining HDAC inhibitors with DNMT inhibitors or miRNA-based therapies have shown synergistic benefits [@combination](https://pubmed.ncbi.nlm.nih.gov/30158527/).
Despite significant advances in understanding epigenetic changes in PSP, numerous questions remain to be addressed.
Causality vs. consequence: The extent to which epigenetic alterations cause disease pathology versus representing secondary responses to tau accumulation remains unclear. Longitudinal studies in prodromal cases and induced pluripotent stem cell (iPSC)-derived models are needed to establish temporal relationships [@ipsc](https://pubmed.ncbi.nlm.nih.gov/30346273/).
Cell-type specificity: The brain comprises diverse cell types with distinct epigenetic landscapes. Single-cell epigenomic approaches will be essential to determine cell-type-specific epigenetic changes and understand how interactions between neurons, astrocytes, microglia, and oligodendrocytes contribute to PSP pathogenesis [@singlecell](https://pubmed.ncbi.nlm.nih.gov/30104667/).
Epigenetic inheritance: The potential for epigenetic changes to be transmitted to daughter cells (mitotic inheritance) or across generations (transgenerational inheritance) remains an important question. While germline inheritance of PSP risk is not established, somatic epigenetic changes in neural progenitor cells may influence brain development and age-related vulnerability [@transgenerational](https://pubmed.ncbi.nlm.nih.gov/30572097/).
Precision epigenetics: The heterogeneity of PSP phenotypes suggests that epigenetic signatures may vary among patients. Comprehensive epigenetic profiling may enable patient stratification for personalized therapeutic approaches [@precision](https://pubmed.ncbi.nlm.nih.gov/31238786/).
Epigenetic modifications represent a fundamental layer of regulatory control that is profoundly altered in PSP. The dysregulation of DNA methylation, histone modifications, and non-coding RNAs contributes to the molecular pathogenesis of PSP through effects on tau metabolism, neuronal survival, neuroinflammation, and cellular stress responses. Understanding these epigenetic changes provides mechanistic insights into how genetic susceptibility and environmental factors interact to drive disease, while also revealing potential therapeutic targets.
The reversible nature of epigenetic modifications offers hope for disease-modifying interventions that could halt or slow the progression of PSP. Ongoing and future clinical trials targeting epigenetic mechanisms, combined with advances in epigenetic profiling technologies, promise to translate these scientific discoveries into clinical benefits for patients with PSP and related tauopathies.