Iksoo Huh

DNA methylation and transcriptional noise

BackgroundDNA methylation is one of the most phylogenetically widespread epigenetic modifications of genomic DNA. In particular, DNA methylation of transcription units (‘gene bodies’) is highly conserved across diverse taxa. However, the functional role of gene body methylation is not yet fully understood. A long-standing hypothesis posits that gene body methylation reduces transcriptional noise associated with spurious transcription of genes. Despite the plausibility of this hypothesis, an explicit test of this hypothesis has not been performed until now.ResultsUsing nucleotide-resolution data on genomic DNA methylation and abundant microarray data, here we investigate the relationship between DNA methylation and transcriptional noise. Transcriptional noise measured from microarrays scales down with expression abundance, confirming findings from single-cell studies. We show that gene body methylation is significantly negatively associated with transcriptional noise when examined in the context of other biological factors.ConclusionsThis finding supports the hypothesis that gene body methylation suppresses transcriptional noise. Heavy methylation of vertebrate genomes may have evolved as a global regulatory mechanism to control for transcriptional noise. In contrast, promoter methylation exhibits positive correlations with the level of transcriptional noise. We hypothesize that methylated promoters tend to undergo more frequent transcriptional bursts than those that avoid DNA methylation.

Staphylococcus aureus Colonization in Acute and Chronic Skin Lesions of Patients with Atopic Dermatitis

Background Staphylococcus aureus (SA) has peculiar abilities to colonize the skin in atopic dermatitis (AD) patients. Objective We sought to determine the colonization rates of SA in acute and chronic skin lesions of AD patients, to find any difference in colonization rates according to age and to find the influences of total immunoglobulin E (IgE) and eosinophil counts to the colonization of SA. Methods We evaluated the total IgE level and eosinophil counts, and cultured SA from the skin lesions of 687 AD patients (131 acute and 556 chronic skin lesions) and 247 control urticaria patients (July 2009 to November 2010; Samsung Medical Center Dermatology Clinic, Seoul, Korea). Results The SA colonization rates were 74%, 38% and 3% in acute, chronic skin lesions and control skin, respectively, and they were increased with age in AD patients. The colonization rate in chronic skin lesions was higher in the high IgE/eosinophilia groups as compared to the normal IgE/eosinophil groups. Conclusion The SA colonization rate was higher in AD patients and especially in acute lesions, and had a tendency to increase with age. As the colonization rates were only higher in the high IgE/eosinophilia groups of chronic skin lesions, we suggested that SA may invade the skin through barrier defects in acute skin lesions, but the colonization in chronic lesions may be orchestrated through many different factors.

IL-31 Serum Protein and Tissue mRNA Levels in Patients with Atopic Dermatitis

Background Severe pruritus is the primary symptom in atopic dermatitis (AD). Recently, the novel cytokine IL-31 has been implicated in the itching associated with AD. Objective We performed this study to determine whether IL-31 serum levels are elevated in AD patients and to better characterize the relationship between serum IL-31 level and other established laboratory parameters. Methods We recruited 55 AD patients, 34 with allergic type AD and 21 with non-allergic type AD, and 38 healthy, non-atopic controls. We checked the laboratory values, severity score, and serum IL-31 levels in all patients and controls, and IL-31 mRNA levels in lesion skin were measured in 13 subjects with AD and in four controls. Results AD patients displayed significantly higher levels of serum IL-31 that were associated with serum IgE, disease severity, and subjective itch intensity. In AD patients, IL-31 mRNA levels from the lesional skin samples also correlated with serum IL-31 level. Conclusion IL-31 is likely one of the many mediators inducing inflammation and pruritus in AD. Although our limited sample size prevents us from making any definitive conclusions, our data demonstrate a strong correlation between IL-31 mRNA level and serum IL-31 protein level, which has never been reported before. Moreover, we found correlations between serum IL-31 level and serum IgE, eosinophil cationic protein, disease severity, and subject itch intensity in certain degrees in AD patients.

HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer

Background Worldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. Methods We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. Results Hepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate ‘metabolic switch’ characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development.

Combined interaction of multi-locus genetic polymorphisms in cytarabine arabinoside metabolic pathway on clinical outcomes in adult acute myeloid leukaemia (AML) patients

Cytarabine arabinoside (ara-C) is the key agent for treating acute myeloid leukaemia (AML). Here, we genotyped 139 single nucleotide polymorphisms (SNPs) within the ara-C transport and metabolic pathway using the Illumina Golden Gate Assay in 97 patients with previously non-treated de novo AML other than M3. DCK rs4694362 (CC genotype) was a significant poor prognostic factor for overall survival (OS) (hazard ratio [HR], 33.202 [95% confidence interval (CI), 4.937-223.273], P<0.0001, P(Bonferroni)=0.017). SLC29A1 rs3734703 (AA or AC genotype) in combination with TYMS rs2612100 (AA genotype) was significantly associated with shorter relapse free survival (RFS) (HR, 17.630 [95% CI, 4.829-64.369], P<0.0001, P(Bonferroni)=0.021). These SNPs showed moderate or large inter ethnic divergence in allele frequencies from African or Caucasian populations. The results of our study suggest that a single SNP and SNP-SNP interactions may help to predict the drug response and provide a guide in developing individualised chemotherapy for AML patients receiving ara-C based chemotherapy.

Association between ST8SIA2 and the Risk of Schizophrenia and Bipolar I Disorder across Diagnostic Boundaries.

Background Findings from family studies and recent genome-wide association studies have indicated overlap in the risk genes between schizophrenia and bipolar disorder (BD). After finding a linkage between the ST8SIA2 (ST8 alpha-N-acetyl-neuraminide alpha-2, 8-sicalyltransferase 2 gene) locus (15q26) and mixed families with schizophrenia and BD, several studies have reported a significant association between this gene and schizophrenia or BD. We investigated the genetic association between ST8SIA2 and both schizophrenia and BD in the Korean population. Methods A total of 582 patients with schizophrenia, 339 patients with BD, and 502 healthy controls were included. Thirty-one tag single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and three other SNPs showing significant associations in previous studies were genotyped. The associations were evaluated by logistic regression analysis using additive, dominant, and recessive genetic models. Results Fourteen of 34 SNPs showed a nominally significant association (p < 0.05) with at least one diagnostic group. These association trends were strongest for the schizophrenia and combined schizophrenia and bipolar I disorder (BD-I) groups. The strongest association was observed in rs11637898 for schizophrenia (p = 0.0033) and BD-I (p = 0.0050) under the dominant model. The association between rs11637898 and the combined schizophrenia and BD-I group (p = 0.0006, under the dominant model) remained significant after correcting for multiple testing. Discussion We identified a possible role of ST8SIA2 in the common susceptibility of schizophrenia and BD-I. However, no association trend was observed for bipolar II disorder. Further efforts are needed to identify a specific phenotype associated with this gene crossing the current diagnostic categories.

Seasonality and its distinct clinical correlates in bipolar II disorder

Seasonality is one of the key features in subjects with mood disorders and is involved in the multi-faceted nature of the clinical course. However, few studies have explored the clinical implications of seasonality in bipolar disorders. We examined the differential effects of seasonality on clinical variables between bipolar I and II disorder (BD I and II). Seasonality was assessed using the Seasonal Pattern Assessment Questionnaire (SPAQ) in 204 subjects with BD I and 308 with BD II. Following the comparisons between BD I and II groups, clinical characteristics related to seasonality were explored. Next, to predict the presence of seasonality, a logistic regression model was applied. The global seasonality score on the SPAQ was significantly higher in the BD II group than in the BD I group. In the BD I group, seasonality was associated with suicide attempt history. In the BD II group, on the other hand, seasonality was associated with female gender, depressive predominance, and premenstrual dysphoric disorder (PMDD). In the regression models, the presence of PMDD and female gender was significantly associated with seasonality in the BD II group. Our findings suggest that high seasonality tendency, a vulnerability maker for cyclic worsening, may contribute to a differential pattern of clinical characteristics in BD II.

Relationship between thyroid-stimulating hormone levels and risk of depression among the general population with normal free T4 levels

OBJECTIVE This study assessed the relationship between thyroid-stimulating hormone (TSH) level and risk of depressive symptom in a population with no clinical or laboratory evidence of thyroid dysfunction. METHODS This retrospective cohort study included 13,017 subjects (7913 males and 5104 females), 17-84 years of age, who underwent health examinations at the hospital. Subjects had a Beck Depression Inventory (BDI) total score of ≤9 and fell within the normal range of free T4 levels at baseline. The association between gender-specific serum TSH tertile at baseline and the development of clinically significant depressive symptom (i.e., ≥19 BDI total score) on the follow-up visit was evaluated using the Cox proportional hazards model, with adjustment for demographic and life style factors. RESULTS The risk of depressive symptom was increased among subjects with the highest tertile TSH level (adjusted hazard ratio [HR], 2.236; 95% confidence interval [CI], 1.443-3.466; p<0.001) as compared with subjects with the lowest tertile in females, but not in males. Even among patients with normal TSH levels, females in the lowest-normal TSH tertile had a higher risk of depressive symptoms (adjusted HR, 2.279; 95% CI, 1.456-3.567; p<0.001) than did those in the highest tertile. The TSH level as a continuous variable significantly predicted the depressive symptoms in females (adjusted HR, 1.402; 95% CI, 1.002-1.812; p=0.027). CONCLUSIONS Our finding suggests that suboptimal thyroid function increases vulnerability to the occurrence of depressive symptom and represents a modifiable risk factor for depression in females.

Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer

Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC.

Bis-class: a new classification tool of methylation status using bayes classifier and local methylation information

BackgroundWhole genome sequencing of bisulfite converted DNA (‘methylC-seq’) method provides comprehensive information of DNA methylation. An important application of these whole genome methylation maps is classifying each position as a methylated versus non-methylated nucleotide. A widely used current method for this purpose, the so-called binomial method, is intuitive and straightforward, but lacks power when the sequence coverage and the genome-wide methylation level are low. These problems present a particular challenge when analyzing sparsely methylated genomes, such as those of many invertebrates and plants.ResultsWe demonstrate that the number of sequence reads per position from methylC-seq data displays a large variance and can be modeled as a shifted negative binomial distribution. We also show that DNA methylation levels of adjacent CpG sites are correlated, and this similarity in local DNA methylation levels extends several kilobases. Taking these observations into account, we propose a new method based on Bayesian classification to infer DNA methylation status while considering the neighborhood DNA methylation levels of a specific site. We show that our approach has higher sensitivity and better classification performance than the binomial method via multiple analyses, including computational simulations, Area Under Curve (AUC) analyses, and improved consistencies across biological replicates. This method is especially advantageous in the analyses of sparsely methylated genomes with low coverage.ConclusionsOur method improves the existing binomial method for binary methylation calls by utilizing a posterior odds framework and incorporating local methylation information. This method should be widely applicable to the analyses of methylC-seq data from diverse sparsely methylated genomes. Bis-Class and example data are provided at a dedicated website (http://bibs.snu.ac.kr/software/Bisclass).