CREBBP
CREB-binding protein (Histone lysine acetyltransferase CREBBP) (EC 2.3.1.48) (Protein-lysine acetyltransferase CREBBP) (EC 2.3.1.-) [CBP]
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Frailty is an age-associated condition, characterized by an inappropriate response to stress that results in a higher frequency of adverse outcomes (e.g., mortality, institutionalization and disability). Some light has been shed over its genetic background, but this is still a matter of debate. In the present study, we used network biology to analyze the interactome of frailty-related genes at different levels to relate them with pathways, clinical deficits and drugs with potential therapeutic implications. Significant pathways involved in frailty: apoptosis, proteolysis, muscle proliferation, and inflammation; genes as FN1, APP, CREBBP, EGFR playing a role as hubs and bottlenecks in the interactome network and epigenetic factors as HIST1H3 cluster and miR200 family were also involved. When connecting clinical deficits and genes, we identified five clusters that give insights into the biology of frailty: cancer, glucocorticoid receptor, TNF-α, myostatin, angiotensin converter enzyme, ApoE, interleukine-12 and -18. Finally, when performing network pharmacology analysis of the target nodes, some compounds were identified as potentially therapeutic (e.g., epigallocatechin gallate and antirheumatic agents); while some other substances appeared to be toxicants that may be involved in the development of this condition.
MeSH Terms
- Aging
- Apoptosis
- Cell Proliferation
- Epigenesis, Genetic
- Frailty
- Genes
- Humans
- Muscle, Smooth
- Pharmacology
- Proteolysis
- Signal Transduction
- Systems Biology
The molecular pathways underlying age-related memory changes remain unclear. There is a substantial genetic contribution to memory performance through life span. A recent study has implicated RbAp48, which mediates its effect on age-related memory decline by interacting with cyclic adenosine monophosphate responsive element binding protein (CREB)1 binding protein and influencing this histone acetylation pathway. To validate these findings, we tested whether genetic variants in RbAp48, CREB1, and CREBBP are associated with memory performance in 3 independent data sets consisting of 2674 cognitively healthy elderly individuals. Genetic variant rs2526690 in the CREBBP gene was significantly associated with episodic memory performance (pmeta = 3.7 × 10(-4)) in a multivariate model adjusted for age, sex, and apolipoprotein E status. Identifying genetic variants that modulate mechanisms of cognitive aging will allow identifying valid targets for therapeutic intervention.
MeSH Terms
- Acetylation
- Aging
- CREB-Binding Protein
- Cognition
- Cohort Studies
- Cyclic AMP Response Element-Binding Protein
- Genetic Association Studies
- Histones
- Humans
- Memory
- Memory, Episodic
- Polymorphism, Single Nucleotide
- Retinoblastoma-Binding Protein 4
Keywords
- Episodic memory performance
- Histone metabolism
- Meta-analysis