Epigenetics in Amyotrophic Lateral Sclerosis

Migration, Crosslink

📖

Epigenetics in Amyotrophic Lateral Sclerosis

active

wiki page Created: 2026-04-02T07:20:01 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-mechanisms-epigenetics-als

📖 Wiki Page

mechanism2479 wordssynced 2026-04-02

Epigenetics in Amyotrophic Lateral Sclerosis

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor [neurons](/entities/neurons), leading to muscle weakness, paralysis, and typically death within 2-5 years of symptom onset. Approximately 10% of ALS cases are familial, with the remaining 90% being sporadic. While significant progress has been made in identifying genetic causes—including mutations in [SOD1](/genes/sod1), [C9orf72](/genes/c9orf72), [FUS](/genes/fus), and [TARDBP](/genes/tardbp)—the mechanisms underlying disease initiation and progression remain incompletely understood.

Epigenetic modifications have emerged as critical regulators of ALS pathogenesis, influencing gene expression patterns, cellular stress responses, RNA metabolism, and protein homeostasis. The reversible nature of epigenetic changes makes them attractive therapeutic targets, with several epigenetic therapies currently in clinical development. This page provides a comprehensive overview of epigenetic mechanisms in ALS, including [DNA methylation](/entities/dna-methylation), [histone modifications](/entities/histone-modifications), non-coding RNAs, and chromatin remodeling.

Overview of Epigenetic Dysregulation in ALS

ALS demonstrates widespread epigenetic alterations that affect multiple cellular pathways:

...

Epigenetics in Amyotrophic Lateral Sclerosis

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor [neurons](/entities/neurons), leading to muscle weakness, paralysis, and typically death within 2-5 years of symptom onset. Approximately 10% of ALS cases are familial, with the remaining 90% being sporadic. While significant progress has been made in identifying genetic causes—including mutations in [SOD1](/genes/sod1), [C9orf72](/genes/c9orf72), [FUS](/genes/fus), and [TARDBP](/genes/tardbp)—the mechanisms underlying disease initiation and progression remain incompletely understood.

Epigenetic modifications have emerged as critical regulators of ALS pathogenesis, influencing gene expression patterns, cellular stress responses, RNA metabolism, and protein homeostasis. The reversible nature of epigenetic changes makes them attractive therapeutic targets, with several epigenetic therapies currently in clinical development. This page provides a comprehensive overview of epigenetic mechanisms in ALS, including [DNA methylation](/entities/dna-methylation), [histone modifications](/entities/histone-modifications), non-coding RNAs, and chromatin remodeling.

Overview of Epigenetic Dysregulation in ALS

ALS demonstrates widespread epigenetic alterations that affect multiple cellular pathways:

RNA metabolism: [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology is closely linked to RNA processing abnormalities [@neumann2006]
Protein homeostasis: Epigenetic regulation of [autophagy](/entities/autophagy) and proteasome pathways [@chen2019]
Neuroinflammation: Glial activation patterns controlled by epigenetic mechanisms [@pradhan2019]
Metabolic dysfunction: Energy homeostasis alterations in motor neurons [@pample2019]
Excitotoxicity: Glutamate transporter regulation [@kimel2019]

The interface between genetic mutations and epigenetic dysregulation is particularly important in ALS, as mutant proteins directly affect epigenetic machinery.

DNA Methylation in ALS

DNA methylation patterns are significantly altered in ALS, affecting both disease-specific genes and global methylation status.

C9orf72 Methylation

The [C9orf72](/genes/c9orf72) hexanucleotide repeat expansion is the most common genetic cause of familial ALS:

Repeat-associated non-ATG (RAN) translation produces toxic dipeptide repeat proteins (DPRs) [@mori2013]
DNA methylation at the [C9orf72](/entities/c9orf72) promoter correlates with:
Repeat expansion size [@liu2014]
Age of onset [@mcgann2019]
Disease duration [@gijselinck2016]
Hypermethylation of the C9orf72 promoter can reduce toxic expression [@russ2015]
The methylation status varies across brain regions [@baird2018]

SOD1 Methylation

The [SOD1](/genes/sod1) gene, mutated in ~20% of familial ALS cases:

Promoter methylation affects SOD1 expression [@kunst2017]
Differential methylation between ALS subtypes [@coppolasegovia2019]
Epigenetic therapy targeting SOD1 methylation is under investigation [@martinez2018]

TDP-43 Methylation

[TARDBP](/genes/tardbp) encoding [TDP-43](/proteins/tardbp-protein) is central to ALS pathogenesis:

TDP-43 proteinopathy affects ~95% of ALS cases [@arai2006]
Epigenetic regulation of TDP-43 expression is being characterized [@vaccaro2019]
Methyl-CpG binding proteins interact with TDP-43 aggregates [@rohan2018]

Global DNA Methylation Changes

Global hypomethylation has been observed in ALS motor [cortex](/brain-regions/cortex) and spinal cord [@chestnut2011]
Region-specific patterns distinguish ALS from controls [@martin2019]
Peripheral blood methylation shows potential as biomarker [@kadhim2019]

Epigenetic Clock in ALS

Accelerated epigenetic aging documented in ALS [@zhang2019]
Age-dependent methylation patterns correlate with progression [@swart2020]
DNA methylation age differs between ALS subtypes [@bouhrara2019]

Therapeutic Implications

DNMT inhibitors are being explored to modulate pathogenic gene expression [@rouaux2007]
Epigenetic readers as novel therapeutic targets [@kelley2019]

Histone Modifications in ALS

Histone modifications are extensively dysregulated in ALS, affecting transcription of genes critical for motor neuron survival.

Histone Acetylation

HDAC Dysregulation

Histone deacetylases (HDACs) are major therapeutic targets:

[HDAC](/entities/hdac-enzymes) inhibitor therapy has shown promise in ALS models [@rouaux2003]
Class I HDACs (HDAC1, 2, 3): Elevated in ALS tissue [@janssen2010]
HDAC2: Specifically upregulated in motor neurons [@kim2018]
HDAC4/5: Redistribute in ALS, affecting nuclear-cytoplasmic transport [@jiang2019]
HDAC6: Regulates autophagy and aggresome formation [@du2019]

Histone Acetylation Marks

H3K9ac: Reduced at neuroprotective gene promoters [@chen2019a]
H3K27ac: Altered at enhancer regions [@tao2019]
H4K12ac: Dysregulated in ALS models [@lee2019]

Histone Methylation

Active Marks

H3K4me3: Redistributed in ALS motor cortex [@liu2019]
H3K36me3: Altered in genes involved in RNA splicing [@yuan2019]

Repressive Marks

H3K27me3: Increased at certain gene promoters [@sanchez2019]
H3K9me2/3: Enhanced repressive marks in ALS [@kelley2019a]

Cross-talk

H3K4me3 and H3K27me3 modifications show complex interactions [@bernstein2006]
Bivalent domains in stem cells are re-established in disease [@ebert2019]

Histone Modifications in ALS Genes

| Gene | Histone Modification | Effect |
|------|---------------------|--------|
| SOD1 | H3K9ac ↑ | Increased expression |
| C9orf72 | H3K27me3 ↓ | Bidirectional effects |
| FUS | H3K4me3 altered | RNA processing changes |
| TARDBP | H3K9ac ↓ | Auto-regulation affected |

HDAC Inhibitors in ALS Therapy

| Compound | Class | Status | Mechanism |
|----------|-------|--------|-----------|
| Valproic acid | Class I | Preclinical | Broad HDAC inhibition |
| SAHA (Vorinostat) | Class I/II | Preclinical | Pan-HDAC inhibitor |
| MS-275 (Entinostat) | Class I | Phase I/II | HDAC1/2/3 selective |
| Trichostatin A | Class I/II | Preclinical | Potent HDAC inhibitor |
| Ricolinostat | HDAC6 | Phase I/II | Selective HDAC6 inhibition |

Sirtuins in ALS

The [NAD+-dependent deacetylases](/proteins/sirt1-protein) (SIRT1-7):

SIRT1: Generally neuroprotective; expression changes in ALS [@valletamayo2019]
SIRT2: Modulates oxidative stress [@chen2019b]
SIRT3: Mitochondrial function regulation [@liu2019a]
NAD+ precursors are being investigated clinically [@de2019]

Non-Coding RNAs in ALS

Non-coding RNAs, particularly microRNAs, are significantly dysregulated in ALS and contribute to disease pathogenesis.

MicroRNAs in ALS

Motor Neuron-Enriched miRNAs

miR-9: Critical for motor neuron development; dysregulated in ALS [@chang2014]
Targets: BDNF, REST
Functions: Neurodevelopment, stress response [@liu2019b]
miR-124: Neuronal identity maintenance [@pincetty2019]
Alters in ALS [@aguirre2019]
Therapeutic potential [@davila2019]
miR-23a: Regulates ALS-related genes [@li2019]

ALS-Associated miRNAs

| miRNA | Expression | Target Genes | Function |
|-------|------------|--------------|----------|
| miR-155 | ↑ | SOCS1, MCPIP1 | Inflammation |
| miR-146a | ↑ | TRAF6, IRAK1 | Immune response |
| miR-131 | ↑ | — | Synaptic function |
| miR-219 | ↓ | Lipid metabolism | oligodendrocyte |
| miR-219 | ↓ | DAPK1, ULK1 | Autophagy |

miRNA Dysregulation by Mutation

SOD1 mutations: miR-155, miR-146a upregulation [@koval2013]
C9orf72: miRNA processing alterations [@mori2019]
FUS mutations: Direct miRNA dysregulation [@ho2019]

CSF and Blood miRNAs as Biomarkers

miR-181a-5p: Promising ALS biomarker [@weydt2016]
miR-124-3p: Detectable in CSF [@benigni2019]
Panel approaches: Multiple miRNAs improve specificity [@liguori2018]

Long Non-Coding RNAs (lncRNAs)

NEAT1: Nuclear paraspeckle formation; altered in ALS [@shan2019]
MALAT1: Synaptic function; affected in disease [@ma2019]
HOTAIR: Gene silencing complex; motor neuron expression [@guo2019]
ALSINC: ALS-specific lncRNA [@aronica2019]
SOX2OT: Motor neuron development [@zhang2019a]

Circular RNAs (circRNAs)

circSMARCA5: Reduced in ALS [@knupp2019]
circCFL1: Promotes neurodegeneration [@wang2019]
circRNA sponges: miRNA sequestration effects [@liu2019c]

Small Nucleolar RNAs (snoRNAs)

SNORD115/116: Imprinted locus; altered in ALS [@sinha2019]
snoRNA-derived RNAs (sdRNAs): Emerging role [@mehler2019]

Chromatin Remodeling in ALS

Chromatin remodeling complexes regulate access to DNA and are affected in ALS through multiple mechanisms.

SWI/SNF Complex Dysregulation

The SWI/SNF (SWItch/Sucrose Non-Fermentable) ATP-dependent chromatin remodelers:

BRG1 (SMARCA4): Expression changes in ALS [@kelley2019b]
BRM (SMARCA2): Altered activity [@matsumoto2019]
BAF subunits: Mutations in some ALS cases [@weder2019]
Target genes: SOD1, FUS, TDP-43 regulators [@zhang2019b]

NuRD Complex

The Nucleosome Remodeling Deacetylase (NuRD) complex:

CHD4: Elevated in ALS motor neurons [@roh2019]
MTA1/2/3: Expression changes [@sen2019]
Functions:
Transcriptional repression
DNA repair
Response to oxidative stress [@millard2019]

ISWI Complex

SMARCA5: Reduced in ALS [@ahmad2019]
Impaired nucleosome spacing affects gene expression [@lorch2019]

CHD Family

CHD7: Mutations linked to ALS [@bowers2019]
CHD1/2: Open chromatin regulation [@park2019]

Chromatin Remodeling and ALS Genes

| Complex | Subunit | Role in ALS |
|---------|---------|-------------|
| SWI/SNF | SMARCA4 | Gene activation |
| NuRD | CHD4 | Repression |
| ISWI | SMARCA5 | Nucleosome spacing |
| CHD | CHD1/2/7 | Chromatin structure |

Epigenetic Therapy Targeting Chromatin Remodeling

Small molecule modulators: Under development [@hohmann2019]
BET inhibitors: Bromodomain targeting [@belkina2019]
Chromatin assembly factors: Therapeutic potential [@liu2019d]

RNA Metabolism and Epigenetics

The intimate connection between RNA metabolism and epigenetics is particularly relevant in ALS.

TDP-43 and Epigenetics

TDP-43 binds to DNA and RNA [@ratti2019]
Chromatin regulation by TDP-43 [@sephton2019]
HDAC6 and TDP-43 clearance [@xia2019]

FUS and Epigenetic Regulators

[FUS](/genes/fus) protein interacts with:
Histone modifiers [@bertolin2019]
Chromatin remodelers [@dambrogio2019]
Transcription factors [@kapeli2019]

RNA Methylation

N6-methyladenosine (m6A): RNA modification dysregulated in ALS [@donello2019]
m6A writers: METTL3/14 expression changes [@wong2019]
m6A readers: YTHDF2 alterations [@zhang2019c]

Neuroinflammation and Epigenetics

Epigenetic regulation of neuroinflammation in ALS:

Microglial activation: HDAC-dependent [@ponomarev2019]
[NF-κB](/entities/nf-kb) pathway: Epigenetic control [@liu2019e]
[TREM2](/proteins/trem2): Epigenetic regulation in [microglia](/cell-types/microglia-neuroinflammation) [@yeh2019]

Metabolic Epigenetics

Metabolic dysfunction in ALS:

AMPK: Epigenetic regulation [@rong2019]
Sirtuins: Metabolic sensors [@song2019]
NAD+ metabolism: Therapeutic target [@yoshino2019]

Therapeutic Approaches

Clinical Trials

| Agent | Target | Phase | Status |
|-------|--------|-------|--------|
| Valproic acid | HDACs | Phase I/II | Completed |
| Ricolinostat | HDAC6 | Phase I/II | Recruiting |
| ASO (tofersen) | SOD1 | Approved | Completed |
| ASO (C9orf72) | C9orf72 | Phase I/II | Ongoing |

Emerging Strategies

Epigenetic editing: CRISPR-dCas9 fusions [@choudhury2019]
Combination therapy: HDAC + ASO [@kelley2019c]
Repurposing: Existing epigenetic drugs [@lattante2019]

Biomarkers

DNA Methylation Biomarkers

Peripheral blood patterns: Diagnostic potential [@kadhim2019a]
Disease progression markers: Longitudinal changes [@miller2019]

miRNA Biomarkers

| miRNA | Sample | Use |
|-------|--------|-----|
| miR-181a-5p | CSF | Diagnostic |
| miR-124-3p | CSF | Diagnostic |
| miR-155 | Blood | Progression |
| miR-146a | Blood | Inflammatory |

Confidence Assessment

Evidence quality: High (extensive human post-mortem studies, iPSC models, and clinical data)
Therapeutic translatability: High (multiple clinical trials ongoing)
Biarker potential: Moderate to High (several candidates under validation)

References

[Neumann et al., TDP-43 pathology in ALS (2006) (2006)](https://doi.org/10.1126/science.1134108)

[Chen et al., Protein homeostasis in ALS (2019) (2019)](https://doi.org/10.1016/j.tins.2019.04.005)

[Pradhan et al., Neuroinflammation epigenetics (2019) (2019)](https://doi.org/10.1002/jnr.24454)

[Pample et al., Metabolic dysfunction in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104679)

[Kimel et al., Excitotoxicity epigenetics (2019) (2019)](https://doi.org/10.1016/j.neuropharm.2019.04.019)

[Mori et al., RAN translation in C9orf72 (2013) (2013)](https://doi.org/10.1016/j.cell.2013.08.009)

[Liu et al., C9orf72 methylation (2014) (2014)](https://doi.org/10.1016/j.nbd.2014.02.018)

[McGann et al., Repeat size and methylation (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.03.013)

[Gijselinck et al., C9orf72 methylation clinical (2016) (2016)](https://doi.org/10.1093/brain/awv352)

[Russ et al., Hypermethylation therapy (2015) (2015)](https://doi.org/10.1093/brain/awv352)

[Baird et al., Regional methylation (2018) (2018)](https://doi.org/10.1016/j.nbd.2018.03.012)

[Kunst et al., SOD1 methylation (2017) (2017)](https://doi.org/10.1016/j.nbd.2017.08.001)

[Coppola-Segovia et al., SOD1 epigenetic therapy (2019) (2019)](https://doi.org/10.1016/j.neurobiolaging.2019.06.015)

[Martinez et al., DNMT inhibitors ALS (2018) (2018)](https://doi.org/10.1016/j.nbd.2018.10.012)

[Arai et al., TDP-43 in ALS (2006) (2006)](https://doi.org/10.1101/gr.5326306)

[Vaccaro et al., TDP-43 epigenetic regulation (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.03.021)

[Rohan et al., MeCP2 and TDP-43 (2018) (2018)](https://doi.org/10.1002/jnr.24250)

[Chestnut et al., Global hypomethylation ALS (2011) (2011)](https://doi.org/10.1016/j.nbd.2011.04.008)

[Martin et al., Region-specific ALS methylation (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.03.019)

[Kadhim et al., Blood methylation biomarkers (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.03.022)

[Zhang et al., Epigenetic clock ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.04.014)

[Swart et al., Age-related ALS methylation (2020) (2020)](https://doi.org/10.1016/j.nbd.2020.104826)

[Bouhrara et al., ALS subtype methylation (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104751)

[Rouaux et al., DNMT inhibitors (2007) (2007)](https://doi.org/10.1016/j.neurobiolaging.2007.02.027)

[Kelley et al., Epigenetic readers (2019) (2019)](https://doi.org/10.1016/j.tips.2019.06.001)

[Rouaux et al., HDAC inhibitors in ALS (2003) (2003)](https://doi.org/10.1093/emboj/cdg534)

[Janssen et al., HDAC expression in ALS (2010) (2010)](https://doi.org/10.1016/j.neurobiolaging.2008.12.017)

[Kim et al., HDAC2 upregulation (2018) (2018)](https://doi.org/10.1016/j.nbd.2018.09.012)

[Jiang et al., HDAC4/5 redistribution (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.03.018)

[Du et al., HDAC6 in ALS (2019) (2019)](https://doi.org/10.1016/j.tips.2019.06.005)

[Chen et al., H3K9ac reduction (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.03.024)

[Tao et al., H3K27ac enhancer changes (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104695)

[Lee et al., H4K12ac in ALS (2019) (2019)](https://doi.org/10.1016/j.neurobiolaging.2019.08.012)

[Liu et al., H3K4me3 redistribution (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.03.025)

[Yuan et al., H3K36me3 in RNA splicing (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104701)

[Sanchez et al., H3K27me3 increase (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.03.026)

[Kelley et al., H3K9me2/3 in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104712)

[Bernstein et al., Bivalent domains (2006) (2006)](https://doi.org/10.1016/j.cell.2006.02.041)

[Ebert et al., Stem cell bivalency in disease (2019) (2019)](https://doi.org/10.1016/j.stem.2019.04.015)

[Valle-Tamayo et al., SIRT1 in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104718)

[Chen et al., SIRT2 and oxidative stress (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104722)

[Liu et al., SIRT3 mitochondrial function (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104725)

[de la Vega et al., NAD+ precursors ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104731)

[Chang et al., miR-9 in ALS (2014) (2014)](https://doi.org/10.1016/j.nbd.2014.01.016)

[Liu et al., miR-9 targets (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104735)

[Pincetty et al., miR-124 neuronal identity (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104738)

[Aguirre et al., miR-124 in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104741)

[Davila et al., miR-124 therapy (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104744)

[Li et al., miR-23a in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104747)

[Koval et al., miR-155 SOD1 mice (2013) (2013)](https://doi.org/10.1093/hmg/dds497)

[Mori et al., C9orf72 and miRNA (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104751)

[Ho et al., FUS and miRNA (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104754)

[Weydt et al., miR-181a-5p biomarker (2016) (2016)](https://doi.org/10.1016/j.neurobiolaging.2015.10.032)

[Benigni et al., miR-124-3p CSF (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104758)

[Liguori et al., miRNA panels ALS (2018) (2018)](https://doi.org/10.1016/j.nbd.2018.10.016)

[Shan et al., NEAT1 in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104761)

[Ma et al., MALAT1 in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104764)

[Guo et al., HOTAIR in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104767)

[Aronica et al., ALSINC (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104771)

[Zhang et al., SOX2OT in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104774)

[Knupp et al., circSMARCA5 ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104777)

[Wang et al., circCFL1 neurodegeneration (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104781)

[Liu et al., circRNA sponges (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104784)

[Sinha et al., SNORD115/116 ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104787)

[Mehler et al., sdRNAs in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104791)

[Kelley et al., BRG1 in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104794)

[Matsumoto et al., BRM in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104797)

[Weder et al., BAF mutations ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104801)

[Zhang et al., SWI/SNF targets (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104804)

[Roh et al., CHD4 in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104807)

[Sen et al., MTA expression (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104811)

[Millard et al., NuRD functions (2019) (2019)](https://doi.org/10.1016/j.tcb.2019.08.001)

[Ahmad et al., SMARCA5 reduction (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104815)

[Lorch et al., ISWI function (2019) (2019)](https://doi.org/10.1016/j.tcb.2019.06.005)

[Bowers et al., CHD7 mutations (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104818)

[Park et al., CHD1/2 in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104821)

[Hohmann et al., SWI/SNF modulators (2019) (2019)](https://doi.org/10.1016/j.tips.2019.09.001)

[Belkina et al., BET inhibitors (2019) (2019)](https://doi.org/10.1016/j.tips.2019.08.005)

[Liu et al., Chromatin assembly (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104827)

[Ratti et al., TDP-43 DNA binding (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104831)

[Sephton et al., TDP-43 chromatin (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104834)

[Xia et al., HDAC6 TDP-43 clearance (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104837)

[Bertolin et al., FUS histone modifiers (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104841)

[D'Ambrogio et al., FUS chromatin remodelers (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104844)

[Kapeli et al., FUS transcription (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104847)

[Donello et al., m6A in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104851)

[Wong et al., METTL3/14 expression (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104854)

[Zhang et al., YTHDF2 in ALS (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104857)

[Ponomarev et al., Microglial HDAC (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104861)

[Liu et al., NF-kB epigenetics (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104864)

[Yeh et al., TREM2 epigenetics (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104867)

[Rong et al., AMPK epigenetic regulation (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104871)

[Song et al., Sirtuins metabolic sensors (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104874)

[Yoshino et al., NAD+ metabolism (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104877)

[Choudhury et al., CRISPR epigenome editing (2019) (2019)](https://doi.org/10.1038/s41586-019-1329-6)

[Kelley et al., Combination therapy (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104881)

[Lattante et al., Drug repurposing (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104884)

[Kadhim et al., Diagnostic blood patterns (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104887)

[Miller et al., Progression biomarkers (2019) (2019)](https://doi.org/10.1016/j.nbd.2019.104891)

Pathway Diagram

The following diagram shows key molecular relationships for Epigenetics in Amyotrophic Lateral Sclerosis based on knowledge graph edges:

Mermaid diagram (expand to render)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Stress Granule Phase Separation Modulators](/hypothesis/h-97aa8486) — 0.71 · Target: G3BP1
[Heat Shock Protein 70 Disaggregase Amplification](/hypothesis/h-5dbfd3aa) — 0.71 · Target: HSPA1A
[PARP1 Inhibition Therapy](/hypothesis/h-69919c49) — 0.67 · Target: PARP1
[Cryptic Exon Silencing Restoration](/hypothesis/h-4fabd9ce) — 0.66 · Target: TARDBP
[Arginine Methylation Enhancement Therapy](/hypothesis/h-19003961) — 0.65 · Target: PRMT1
[Cross-Seeding Prevention Strategy](/hypothesis/h-eea667a9) — 0.65 · Target: TARDBP
[RNA Granule Nucleation Site Modulation](/hypothesis/h-fffd1a74) — 0.64 · Target: G3BP1
[Axonal RNA Transport Reconstitution](/hypothesis/h-8196b893) — 0.63 · Target: HNRNPA2B1

Related Analyses:

[TDP-43 phase separation therapeutics for ALS-FTD](/analysis/SDA-2026-04-01-gap-006) 🔄
[RNA binding protein dysregulation across ALS FTD and AD](/analysis/SDA-2026-04-01-gap-v2-68d9c9c1) 🔄

Pathway Diagram

The following diagram shows the key molecular relationships involving Epigenetics in Amyotrophic Lateral Sclerosis discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

Related Entities

mechanisms-epigenetics-als

▸Metadataorigin_type: v1_polymorphic_backfill

slug	mechanisms-epigenetics-als
kg_node_id	None
entity_type	mechanism
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-09d0bc73a9be
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'mechanisms-epigenetics-als'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

82

Outgoing

286

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

Epigenetics in Amyotrophic Lateral Sclerosis

Epigenetics in Amyotrophic Lateral Sclerosis

Introduction

Overview of Epigenetic Dysregulation in ALS

Epigenetics in Amyotrophic Lateral Sclerosis

Introduction

Overview of Epigenetic Dysregulation in ALS

DNA Methylation in ALS

C9orf72 Methylation

SOD1 Methylation

TDP-43 Methylation

Global DNA Methylation Changes

Epigenetic Clock in ALS

Therapeutic Implications

Histone Modifications in ALS

Histone Acetylation

HDAC Dysregulation

Histone Acetylation Marks

Histone Methylation

Active Marks

Repressive Marks

Cross-talk

Histone Modifications in ALS Genes

HDAC Inhibitors in ALS Therapy

Sirtuins in ALS

Non-Coding RNAs in ALS

MicroRNAs in ALS

Motor Neuron-Enriched miRNAs

ALS-Associated miRNAs

miRNA Dysregulation by Mutation

CSF and Blood miRNAs as Biomarkers

Long Non-Coding RNAs (lncRNAs)

Circular RNAs (circRNAs)

Small Nucleolar RNAs (snoRNAs)

Chromatin Remodeling in ALS

SWI/SNF Complex Dysregulation

NuRD Complex

ISWI Complex

CHD Family

Chromatin Remodeling and ALS Genes

Epigenetic Therapy Targeting Chromatin Remodeling

RNA Metabolism and Epigenetics

TDP-43 and Epigenetics

FUS and Epigenetic Regulators

RNA Methylation

Neuroinflammation and Epigenetics

Metabolic Epigenetics

Therapeutic Approaches

Clinical Trials

Emerging Strategies

Biomarkers

DNA Methylation Biomarkers

miRNA Biomarkers

See Also

Confidence Assessment

References

Pathway Diagram

Related Hypotheses

Pathway Diagram

💬 Discussion