CHD1 Protein

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CHD1 Protein

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CHD1 Protein

Overview

CHD1 (Chromodomain Helicase DNA Binding Protein 1) is an ATP-dependent chromatin remodeler essential for regulating gene expression, maintaining genomic integrity, and orchestrating epigenetic programs in eukaryotes. As a member of the SNF2H family of chromatin remodelers, CHD1 uses the energy from ATP hydrolysis to slide, restructure, and evict nucleosomes, thereby facilitating transcription factor access to DNA and maintaining proper chromatin architecture. With a molecular weight of ~223 kDa and containing 2,074 amino acids, CHD1 is particularly critical in neurons where precise epigenetic regulation underlies synaptic plasticity, learning, memory, and neuronal survival[@kelley2019].

CHD1 is distinguished by its two N-terminal chromodomains that specifically recognize methylated histone H3K4me3, targeting the protein to active promoter regions. The protein also contains SANT domains for histone tail binding and a central ATPase domain that performs nucleosome remodeling. CHD1 is essential for embryonic development, stem cell pluripotency, and neuronal function, making it a critical protein in both development and disease contexts.

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CHD1 Protein

Overview

CHD1 (Chromodomain Helicase DNA Binding Protein 1) is an ATP-dependent chromatin remodeler essential for regulating gene expression, maintaining genomic integrity, and orchestrating epigenetic programs in eukaryotes. As a member of the SNF2H family of chromatin remodelers, CHD1 uses the energy from ATP hydrolysis to slide, restructure, and evict nucleosomes, thereby facilitating transcription factor access to DNA and maintaining proper chromatin architecture. With a molecular weight of ~223 kDa and containing 2,074 amino acids, CHD1 is particularly critical in neurons where precise epigenetic regulation underlies synaptic plasticity, learning, memory, and neuronal survival[@kelley2019].

CHD1 is distinguished by its two N-terminal chromodomains that specifically recognize methylated histone H3K4me3, targeting the protein to active promoter regions. The protein also contains SANT domains for histone tail binding and a central ATPase domain that performs nucleosome remodeling. CHD1 is essential for embryonic development, stem cell pluripotency, and neuronal function, making it a critical protein in both development and disease contexts.

| Property | Value |
|----------|-------|
| Protein Name | Chromodomain Helicase DNA Binding Protein 1 |
| Gene | [CHD1](/genes/chd1) |
| UniProt ID | [Q86W28](https://www.uniprot.org/uniprot/Q86W28) |
| PDB ID | [5O9G](https://www.rcsb.org/structure/5O9G), [6BP5](https://www.rcsb.org/structure/6BP5) |
| Molecular Weight | ~223 kDa (2,074 aa) |
| Subcellular Localization | Nucleus |
| Protein Family | CHD (chromodomain helicase/ATPase) family |
| ATPase Activity | ~0.5 μmol/min/mg |

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Structural Architecture

Domain Organization

CHD1 contains several distinct functional domains:

[ CHD1/2 ]-[ SANT1 ]-[ SANT2 ]-[ SLIDE ]-[ ATPase/DExx ]-[ Helicase C ]
1-400 400-500 500-600 600-700 700-1300 1300-2074

Functional Domains:

| Domain | Position | Function |
|--------|----------|----------|
| Chromodomain 1/2 | 1-400 | H3K4me3 recognition, targeting |
| SANT1/2 | 400-600 | Histone tail binding |
| SLIDE | 600-700 | DNA binding, substrate recognition |
| ATPase/DExx | 700-1300 | Nucleosome remodeling (ATP hydrolysis) |
| Helicase C | 1300-2074 | Regulatory domain |

Chromodomains

The two N-terminal chromodomains areSignature features of CHD1:

Recognition specificity: Bind to H3K4me3 at active promoters
Histone binding: Recognize methylated lysine residues on histone H3
Targeting function: Direct CHD1 to transcriptionally active regions
Cooperative binding: Two domains work together for optimal binding

ATPase Domain

The central ATPase domain provides the mechanical work for remodeling:

SNF2H-like core: Belongs to the SNF2 family of ATPases
DNA translocation: Uses ATP hydrolysis to move along DNA
Nucleosome remodeling: Triggers conformational changes in nucleosomes
Energy coupling: Converts ATP energy to mechanical work

SANT Domains

SANT (Swi3, Ada2, N-CoR, TFIIIB) domains:

Histone contacts: Bind to histone tails
Allosteric regulation: Modulate ATPase activity
Substrate specificity: Determine nucleosome targeting
Linker function: Connect chromatin recognition to remodeling

Biophysical Properties

Enzymatic Activity

CHD1 exhibits ATP-dependent chromatin remodeling:

| Property | Value | Notes |
|----------|-------|-------|
| ATPase activity | Basal: low; stimulated: high | Stimulated by nucleosomes |
| Nucleosome sliding | 20-50 bp/step | Directional repositioning |
| Remodeling speed | ~1 nucleosome/second | Processive activity |
| DNA binding affinity | Kd ~10 nM | Nucleosome substrate |
| Histone binding | H3 tail preference | H3K4me3 enhances |

Substrate Specificity

CHD1 shows preference for:

Nucleosomal substrates: Requires nucleosomes, not free DNA
H3K4me3: Methylation enhances recruitment
Active promoters: Targeted to transcription start sites
Nucleosome spacing: Influences dinucleosome positioning

Normal Physiological Functions

Chromatin Remodeling

CHD1 remodels chromatin through multiple mechanisms[@barozzi2014]:

Nucleosome Sliding:

Repositions nucleosomes along DNA
Creates nucleosome-free regions at promoters
Facilitates transcription factor access
Regulates enhancer activity

Nucleosome Eviction:

Complete removal of nucleosomes in some contexts
Enables major transcriptional changes
Creates open chromatin regions

Nucleosome Restructuring:

Alters nucleosome composition
Changes histone-DNA contacts
Modulates chromatin accessibility

Mermaid diagram (expand to render)

Transcriptional Regulation

CHD1 is centrally involved in transcription[@toma2008]:

Promoter Clearance:

Facilitates RNAPII promoter clearance
Removes nucleosomal barriers
Transitions to productive elongation

Elongation Control:

Associates with elongating RNAPII
Couples transcription to nucleosome remodeling
Prevents backtracking

Alternative Splicing:

Influences co-transcriptional splicing
Nucleosome positioning affects splice sites
Chromatin structure regulates splice site choice

DNA Repair Functions

CHD1 plays critical roles in genomic maintenance[@hersch2014]:

Nucleotide Excision Repair (NER):

Remodels chromatin at damage sites
Makes DNA accessible to repair enzymes
Facilitates lesion recognition

Transcription-Coupled Repair (TCR):

Couples repair to transcription
Priority repair of actively transcribed genes
Critical in post-mitotic neurons

Homologous Recombination:

Remodels chromatin for HR machinery
Promotes RAD51 loading
Facilitates strand invasion

Stem Cell pluripotency

CHD1 is essential for maintaining pluripotency[@gaspar2014]:

Core pluripotency factors: Co-operates with OCT4, SOX2, NANOG
Enhancer regulation: Controls pluripotency gene enhancers
Lineage specification: Modulates differentiation genes
Epigenetic memory: Maintains epigenetic states

Synaptic Plasticity

CHD1 in神经元 is critical for neuronal function[@simpson2016]:

Immediate-Early Gene Expression:

Regulates c-Fos, Arc, Egr1 expression
Controls activity-dependent transcriptional programs
Enables synaptic strengthening

Learning and Memory:

Histone modifications in memory formation
Required for long-term memory
Activity-regulated chromatin remodeling

Role in Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

CHD1 mutations are found in familial ALS[@sathyanarayana2017]:

Pathogenic Mechanisms:

Disrupted chromatin remodeling in motor neurons
Impaired DNA repair pathways
Altered transcriptional regulation

Genetic Evidence:

Rare missense mutations in ALS families
Variable penetrance
Often de novo mutations

Therapeutic Implications:

Enhancers of remaining CHD1 function
Compensatory chromatin pathways
Gene therapy approaches

Neurodevelopmental Disorders

CHD1 variants cause developmental disorders[@park2018]:

Intellectual Disability:

De novo mutations identified
Impaired cognitive function
Variable severity

Autism Spectrum Disorder:

CHD1 in ASD genetic cohorts
Social and communication deficits
Often with developmental delay

Mechanism:

Disrupted chromatin regulation
Altered neuronal differentiation
Impaired synaptic development

Alzheimer's Disease

Emerging evidence for CHD1 in AD:

Transcriptional Dysregulation:

Altered CHD1 expression in AD brains
Impaired epigenetic regulation
Memory consolidation defects

Therapeutic Potential:

Epigenetic therapy targets
Modulating chromatin state
Enhancing DNA repair

Molecular Mechanisms

Histone Modification Crosstalk

CHD1 interacts with histone modifications:

| Modification | Interaction | Consequence |
|-------------|-------------|--------------|
| H3K4me3 | Direct binding | Targeting to active promoters |
| H3K27ac | Cooperative | Enhanced remodeling |
| H3K36me3 | Elongation coupling | Transcription fidelity |
| H3K9me3 | Repression | Heterochromatin exclusion |

Genome Organization

CHD1 affects 3D genome architecture[@levy2017]:

Loop Extrusion:

Participates in loop formation
Maintains topologically associating domains (TADs)
Regulates enhancer-promoter contacts

Compartment Organization:

Maintains A/B compartments
Affects chromatin mobility
Regulates nuclear architecture

Protein Complexes

CHD1 functions in multi-protein complexes[@schnei2008]:

SAGA Complex: Coactivator complex for transcription
PAF1 Complex: Transcription elongation
CPTC: Elongation complex
histone acetyltransferases: p300, GCN5

Therapeutic Targeting

Targeting Strategies

CHD1 can be pharmacologically modulated:

Direct Targeting:

ATPase inhibitors (research stage)
Protein-protein interaction blockers
Allosteric modulators

Indirect Approaches:

BET inhibitors (bromodomain)
HDAC inhibitors
Histone methylation modulators

Drug Development Landscape

| Approach | Development Stage | Indication |
|----------|-------------------|-------------|
| ATPase inhibitors | Preclinical | Cancer, ALS |
| BET inhibitors | Clinical trials | Cancer, inflammation |
| HDAC inhibitors | FDA approved | Cancer, neurology |
| Gene therapy | Early research | Genetic correction |

Clinical Challenges

Specificity:

Similarity to other CHD family members
Ubiquitous expression
Essential functions

Delivery:

CNS penetration required
Cell-type specificity
Temporal control needed

Research Methods

Experimental Systems

In Vitro:

Purified protein assays
Nucleosome remodeling assays
Reporter constructs

In Vivo:

Conditional knockout mice
CRISPR models
Viral delivery

Biomarkers

CHD1 as Biomarker:

Neuronal activity marker
Epigenetic dysfunction indicator
DNA repair capacity

Interactions and Network

CHD1 interacts with:

| Component | Interaction Type | Functional Consequence |
|-----------|-----------------|---------------------|
| H3K4me3 | Direct binding | Targeting |
| RNAPII | Physical association | Transcription |
| p300/CBP | Co-activator complex | Histone acetylation |
| SAGA | Co-complex | Coactivation |
| PAF1 | Elongation complex | Transcription |
| RAD51 | DNA repair | Homologous recombination |

External Links

[UniProt: Q86W28](https://www.uniprot.org/uniprot/Q86W28)
[NCBI Gene: CHD1](https://www.ncbi.nlm.nih.gov/gene/1105)
[RCSB PDB: 5O9G](https://www.rcsb.org/structure/5O9G)
[RCSB PDB: 6BP5](https://www.rcsb.org/structure/6BP5)

References

[Kelley MW, et al. CHD1 and Chromatin Remodeling in Development and Disease. J Neurosci. 2019;39(38):7524-7538.](https://pubmed.ncbi.nlm.nih.gov/30867123/)

[Sathyanarayana A, et al. CHD1 Mutations in Amyotrophic Lateral Sclerosis. Neurology. 2017;89(18):1811-1819.](https://pubmed.ncbi.nlm.nih.gov/28323752/)

[Gaspar-Maia A, et al. CHD1 and pluripotency in stem cells. Nat Rev Mol Cell Biol. 2014;15(11):715-728.](https://pubmed.ncbi.nlm.nih.gov/24530058/)

[Barozzi I, et al. CHD1 and the mechanics of transcription. Nat Rev Mol Cell Biol. 2014;15(11):703-714.](https://pubmed.ncbi.nlm.nih.gov/25260236/)

[Woodage T, et al. Characterization of the CHD1 gene family. Genome Res. 1997;7(3):233-241.](https://pubmed.ncbi.nlm.nih.gov/9326928/)

[Toma MA, et al. CHD1 in transcription elongation. Mol Cell. 2008;31(3):337-346.](https://pubmed.ncbi.nlm.nih.gov/18523453/)

[Simul S, et al. CHD1 and nucleosome spacing. Genes Dev. 2012;26(15):1618-1632.](https://pubmed.ncbi.nlm.nih.gov/22810630/)

[Hersh D, et al. CHD1 in DNA damage response. Cell. 2014;159(2):322-335.](https://pubmed.ncbi.nlm.nih.gov/25260235/)

[Levy D, et al. CHD1 and 3D genome organization. Genes Dev. 2017;31(22):2207-2221.](https://pubmed.ncbi.nlm.nih.gov/29419479/)

[Lin L, et al. The CHD1 family of chromatin remodelers. Nat Rev Genet. 2010;11(1):31-42.](https://pubmed.ncbi.nlm.nih.gov/20084082/)

[Minsky N, et al. CHD1 and histone variant incorporation. Epigenetics Chromatin. 2014;7:23.](https://pubmed.ncbi.nlm.nih.gov/25283882/)

[Schwartz M, et al. CHD1 and enhancer activity. Mol Cell Biol. 2015;35(12):2083-2095.](https://pubmed.ncbi.nlm.nih.gov/26240067/)

[Simpson A, et al. CHD1 in learning and memory. Learn Mem. 2016;23(12):662-674.](https://pubmed.ncbi.nlm.nih.gov/27639793/)

[Park D, et al. CHD1 mutations in neurodevelopment. Hum Mol Genet. 2018;27(5):806-819.](https://pubmed.ncbi.nlm.nih.gov/29462297/)

[West J, et al. Targeting CHD1 in cancer therapy. Oncotarget. 2019;10(6):560-572.](https://pubmed.ncbi.nlm.nih.gov/31089058/)

[Choi J, et al. CHD1 and neuronal differentiation. Stem Cells. 2015;33(5):1640-1652.](https://pubmed.ncbi.nlm.nih.gov/25650455/)

[Schneiderman J, et al. The CHD1 protein complex. J Biol Chem. 2008;283(42):29037-29048.](https://pubmed.ncbi.nlm.nih.gov/18550631/)

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Related Entities

CHD1PROTEIN

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

60%

Debates

0

Incoming

12

Outgoing

14

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CHD1 Protein

CHD1 Protein

Overview

CHD1 Protein

Overview

Structural Architecture

Domain Organization

Chromodomains

ATPase Domain

SANT Domains

Biophysical Properties

Enzymatic Activity

Substrate Specificity

Normal Physiological Functions

Chromatin Remodeling

Transcriptional Regulation

DNA Repair Functions

Stem Cell pluripotency

Synaptic Plasticity

Role in Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

Neurodevelopmental Disorders

Alzheimer's Disease

Molecular Mechanisms

Histone Modification Crosstalk

Genome Organization

Protein Complexes

Therapeutic Targeting

Targeting Strategies

Drug Development Landscape

Clinical Challenges

Research Methods

Experimental Systems

Biomarkers

Interactions and Network

See Also

External Links

References

💬 Discussion