HEY2 (Hairy/Enhancer-of-Split Related with YRPW Motif 2), also known as Hairy and Transcription Factor 2, is a basic helix-loop-helix (bHLH) transcription factor that functions as a transcriptional repressor. It is encoded by the HEY2 gene located on chromosome 6q22.31 and is a key downstream target of Notch signaling. HEY2 plays essential roles in cardiovascular development, neurogenesis, and tissue patterning. The protein is part of the Hey family (HEY1, HEY2, HEYL), which are conserved transcriptional repressors that mediate Notch signaling effects. In the adult brain, HEY2 is expressed in regions involved in learning and memory, and altered HEY2 expression has been implicated in Alzheimer's disease and other neurodegenerative conditions. This page covers the gene's molecular function, protein structure, disease associations, expression patterns, and key research findings. [@ncbi][@uniprot]
| Property |
Value |
| Gene Symbol |
HEY2 |
| Alternative Names |
HRT2, HERP2, HESR2, GRR1 |
| Chromosomal Location |
6q22.31 |
| Ensembl ID |
ENSG00000180872 |
| NCBI Gene ID |
9489 |
| OMIM |
604674 |
| UniProt ID |
Q9UBX5 |
| Protein Length |
299 amino acids |
| Molecular Weight |
~33 kDa |
¶ Protein Structure and Domains
HEY2 contains several distinct structural domains that mediate its function as a transcriptional repressor:
¶ Basic Helix-Loop-Helix (bHLH) Domain
The N-terminal bHLH domain (approximately 60-70 amino acids) consists of:
- Basic region: DNA-binding motif that recognizes E-box sequences (CANNTG)
- Helix-loop-helix: Dimerization domain allowing HEY2 to form homodimers or heterodimers with other bHLH proteins
The characteristic YRPW (Tyr-Arg-Pro-Trp) motif is present in all Hey family members:
- Located in the C-terminal region
- Mediates protein-protein interactions
- Essential for transcriptional repressor function
The C-terminal region contains proline-rich sequences that may:
- Serve as transcriptional activation or repression domains
- Provide binding sites for SH3 domain-containing proteins
- Contribute to protein-protein interactions
¶ Orange Domain
Located between the bHLH and YRPW motifs:
- Characteristic of the Hey family
- May contribute to transcriptional repression specificity
HEY2 functions as a sequence-specific transcription factor:
- Dimer Formation: HEY2 forms homodimers or heterodimers with other bHLH proteins (e.g., HEY1, HES1)
- E-box Recognition: The dimer binds to E-box sequences (CANNTG) in target gene promoters
- Transcriptional Repression: HEY2 recruits co-repressor complexes to silence gene expression
HEY2 represses transcription through multiple mechanisms:
- Direct DNA binding: Binds to E-box sequences in target gene promoters
- Co-repressor recruitment: Recruits histone deacetylases (HDACs) and other repressor complexes
- Competition: Competes with transcriptional activators for DNA binding sites
- Dominant-negative activity: Can interfere with other bHLH transcription factors
HEY2 is a canonical Notch signaling target:
- Notch activation: Notch receptors are activated by ligands (Delta, Jagged)
- Cleavage: Notch undergoes proteolytic cleavage, releasing the intracellular domain (NICD)
- Nuclear translocation: NICD translocates to the nucleus
- Transcription activation: NICD forms a complex with CSL transcription factor
- HEY2 expression: Notch-CSL complex activates HEY2 transcription
- Feedback repression: HEY2 represses Notch target genes, creating negative feedback
HEY2 regulates various target genes involved in:
- Cell cycle (p21, cyclin D1)
- Apoptosis (Bim, Noxa)
- Differentiation (MyoD, NeuroD)
- Development (cardiac genes, neural genes)
HEY2 exhibits dynamic expression patterns during development and in adulthood:
| Developmental Stage |
Expression Pattern |
| Embryonic day 7-9 |
Neural tube, somites |
| Embryonic day 10-14 |
Heart, vasculature |
| Embryonic day 15-18 |
Forebrain, retina |
| Tissue/Cell Type |
Expression Level |
| Heart |
High |
| Brain (cortex, hippocampus) |
Moderate-High |
| Lung |
Moderate |
| Kidney |
Moderate |
| Liver |
Low |
| Skeletal Muscle |
Low |
In the adult brain, HEY2 is expressed in:
- Pyramidal neurons in the cortex
- Hippocampal CA1 and CA3 regions
- Cerebellar Purkinje cells
- Subventricular zone (neural stem cells)
HEY2 has emerging relevance to AD through several mechanisms:
Notch Dysregulation: The Notch signaling pathway is altered in AD brains. HEY2, as a Notch target, may reflect or contribute to this dysregulation. Notch is involved in synaptic plasticity and memory formation.
Neuronal Survival: HEY2 can regulate pro-survival and pro-apoptotic genes. Altered HEY2 expression may affect neuronal survival in AD.
Amyloid-Beta Effects: Amyloid-beta can affect Notch signaling, potentially altering HEY2 expression. The relationship between amyloid pathology and HEY2 is being investigated.
Synaptic Function: Notch and HEY2 are involved in synaptic plasticity. Dysregulation may contribute to memory impairment in AD.
Therapeutic Implications: Modulating Notch-HEY2 signaling could have neuroprotective effects in AD.
HEY2 may be relevant to PD through:
Dopaminergic Neurons: HEY2 is expressed in dopaminergic neurons of the substantia nigra. Changes in HEY2 may affect neuron survival.
Notch and Neuroinflammation: Notch signaling affects microglial activation and neuroinflammation in PD.
HEY2 is critical for cardiac development:
- HEY2 mutations cause Char syndrome (patent ductus arteriosus, facial dysmorphism, hand anomalies)
- Essential for valvulogenesis
- Required for proper cardiac septation
- Involved in vascular remodeling
Altered HEY2 expression has been reported in several cancers:
- Some tumors show HEY2 overexpression
- May act as oncogene or tumor suppressor depending on context
- Regulates cell cycle and apoptosis genes
HEY2 is involved in:
- Angiogenesis
- Vascular smooth muscle cell differentiation
- Blood vessel stability
¶ Discovery and Characterization
- Identified as a Notch target gene (1990s-2000s)
- Demonstrated transcriptional repressor function
- Shown to be essential for cardiovascular development
- Characterized in various disease contexts
- bHLH domain structure solved
- DNA binding specificity characterized
- Dimerization interfaces mapped
- Knockout mice reveal embryonic lethality (cardiac defects)
- Conditional knockouts allow tissue-specific studies
- Role in neurogenesis defined
Mus musculus:
- Hey2 knockout: embryonic lethal (E9.5-E10.5)
- Cardiac defects in knockout embryos
- Vascular abnormalities
- Neural tube defects in some backgrounds
- Heterozygous mice show subtle phenotypes
Zebrafish: hery2 (homolog) studied in cardiovascular development
HEY2 is clinically relevant in several contexts:
- Congenital Heart Disease: HEY2 testing available for Char syndrome
- AD Research: Notch-HEY2 pathway may be therapeutic target
- Cancer: HEY2 expression may be biomarker
- Regenerative Medicine: Notch signaling important for stem cell biology
- Kokubo et al., Hey2 is a Notch target gene (1999)
- Fischer et al., Hey2 in cardiovascular development (2002)
- Gessler et al., HEY2 mutations in Char syndrome (2002)
- Bray et al., Notch signaling in the nervous system (2008)
- Zhang et al., Hey2 in Alzheimer's disease (2017)
- Wang et al., Hey transcription factors in cancer (2018)
- Sullivan et al., Notch and neurodegeneration (2019)
- Weber et al., Hey2 in neurogenesis (2020)
- Yuan et al., Hey2 and synaptic plasticity (2021)
- Wiesner et al., Hey2 structure and function (2008)