RESUMO
The liver X receptor agonist, GW3965, improves cognition in Alzheimer's disease (AD) mouse models. Here, we determined if short-term GW3965 treatment induces changes in the DNA methylation state of the hippocampus, which are associated with cognitive improvement. Twenty-four-month-old triple-transgenic AD (3xTg-AD) mice were treated with GW3965 (50 mg/kg/day for 6 days). DNA methylation state was examined by modified bisulfite conversion and hybridization on Illumina Infinium Methylation BeadChip 450 k arrays. The Morris water maze was used for behavioral analysis. Our results show in addition to improvement in cognition methylation changes in 39 of 13,715 interrogated probes in treated 3xTg-AD mice compared with untreated 3xTg-AD mice. These changes in methylation probes include 29 gene loci. Importantly, changes in methylation status were mainly from synapse-related genes (SYP, SYN1, and DLG3) and neurogenesis-associated genes (HMGB3 and RBBP7). Thus, our results indicate that liver X receptors (LXR) agonist treatment induces rapid changes in DNA methylation, particularly in loci associated with genes involved in neurogenesis and synaptic function. Our results suggest a new potential mechanism to explain the beneficial effect of GW3965.
Assuntos
Doença de Alzheimer/metabolismo , Benzoatos/farmacologia , Benzilaminas/farmacologia , Metilação de DNA/efeitos dos fármacos , Neurogênese , Receptores Nucleares Órfãos/agonistas , Sinapses/efeitos dos fármacos , Doença de Alzheimer/genética , Animais , Feminino , Proteína HMGB3/genética , Proteína HMGB3/metabolismo , Receptores X do Fígado , Camundongos , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , Proteína 7 de Ligação ao Retinoblastoma/genética , Proteína 7 de Ligação ao Retinoblastoma/metabolismo , Sinapses/metabolismo , Sinaptofisina/genética , Sinaptofisina/metabolismoRESUMO
Gastric cancer is a major health problem worldwide; it is the second most common cause of cancer death in the world. Recent studies indicate that the high-mobility group (HMG) of chromosomal proteins is associated with cancer progression. However, HMGB3 has been little studied. We analyzed the co-expression network between HMGB3 and differentially-expressed genes in the GSE17187 database, identifying the relevant transcription factors, and the conserved domain of HMGB3 to understand the underlying regulation mechanisms involved in gastric cancer. Thirty-one relationships between 11 differentially-expressed genes were included in a co-expression network; many of these genes have been identified as related to cancer, including TBX5 and TFR2. Further analysis identified nine transcription factors, these being GATA3, MZF1, GATA1, GATA2, SRY, REL, NFYB, NFYC, and NFYA, which could interact with HMGB3 to regulate target gene expression and consequently regulate gastric cancer cell proliferation, migration and invasion. The HMG-box domain was very similar in various species, with only a few amino acid changes, indicating conserved functions in HMG-box. This information helps to provide insight into the molecular mechanisms of HMGB3 in human gastric cancer.