PMID:27058954

Citation	Sung, HY, Choi, BO, Jeong, JH, Kong, KA, Hwang, J and Ahn, JH Amyloid Beta-Mediated Hypomethylation of Heme Oxygenase 1 Correlates with Cognitive Impairment in Alzheimer's Disease. PLoS ONE 11:e0153156
Abstract	To identify epigenetically regulated genes involved in the pathogenesis of Alzheimer's disease (AD) we analyzed global mRNA expression and methylation profiles in amyloid precursor protein (APP)-Swedish mutant-expressing AD model cells, H4-sw and selected heme oxygenase-1 (HMOX1), which is associated with pathological features of AD such as neurofibrillary tangles and senile plaques. We examined the epigenetic regulatory mechanism of HMOX1 and its application as a diagnostic and prognostic biomarker for AD. Our results show that HMOX1 mRNA and protein expression was approximately 12.2-fold and 7.9-fold increased in H4-sw cells, respectively. Increased HMOX1 expression was also detected in the brain, particularly the hippocampus, of AD model transgenic mice. However, the methylation of specific CpG sites within its promoter, particularly at CpG located -374 was significantly decreased in H4-sw cells. Treatment of neuroglioma cells with the demethylating agent 5-aza-2'-deoxycytidine resulted in reduced methylation of HMOX1 promoter accompanied by enhanced HMOX1 expression strongly supporting DNA methylation-dependent transcriptional regulation of HMOX1. Toxic Aβ-induced aberrant hypomethylation of HMOX1 at -374 promoter CpG site was correlated with increased HMOX1expression. In addition to neuroglioma cells, we also found Aβ-induced epigenetic regulation of HMOX1 in human T lymphocyte Jurkat cells. We evaluated DNA methylation status of HMOX1 at -374 promoter CpG site in blood samples from AD patients, patients with mild cognitive impairment (MCI), and control individuals using quantitative methylation-specific polymerase chain reaction. We observed lower methylation of HMOX1 at the -374 promoter CpG site in AD patients compared to MCI and control individuals, and a correlation between Mini-Mental State Examination score and demethylation level. Receiver operating characteristics analysis revealed good discrimination of AD patients from MCI patients and control individuals. Our findings suggest that the methylation status of HMOX1 at a specific promoter CpG site is related to AD progression.
Links	PubMed Online version:10.1371/journal.pone.0153156
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:HMOX1		GO:0004392: heme oxygenase (decyclizing) activity	ECO:0000316:	PMID:27058954 InterPro:IPR016084 UniProtKB:P09601 (HMOX1_HUMAN)	F		A group of experimental scientists analyzed the global mRNa expression and the methylation profiles in APP to identify the genes involved to be able to treat Alzheimer's. They particularly focused on the functions of protein heme oxygenase 1 found in gene HMOX1. The group of researchers basically evaluated the how important the protein HMOX1 is in Alzheimer's. For this experiment, the scientists used human blood and lab mice. This was an extremely extensive project as plenty of processes were involved. The processes were: - RNA extraction (qRT), quantitative reverse-transcription polymerase chain reaction (PCR), Transcriptome sequential analysis, Western blot analysis, genomic DNA extraction, genomic DNA modification, Methylation microarray, Quantitative methylation-specific PCR (qMSP), bisulfite sequential analysis, deoxycytidine treatment, amyloid preparation and treatment and in the end Statistical Analysis. Figure 1 shows the HMOX1 expression up-regulated in an APP-mutant cell line and transgenic mice.The effect of the protein is heavily evaluated by the virtue of its effects on the minds of mice. Alzheimer's is a disease that is becoming increasingly common in humans and therefore, this experiment is significant in understanding the pros and cons of this enzyme so that we can come up with better treatments for this amnesic disease. The results of this experiment showed that heme oxygenase 1 is in fact directly correlated with Alzheimer's as shown from the results in Figures 1,2,3,4,5 and 6. The statistical analysis also convinced the researchers that HMOX1 is a key factor in cognitive impairment of Alzheimer's.	complete CACAO 11564

References

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