Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Molecular signatures differentiate immune states in Type 1 Diabetes families

ABSTRACT: The complex milieu of inflammatory mediators associated with many diseases is often too dilute to directly measure in the periphery, necessitating development of more sensitive measurements suitable for mechanistic studies, earlier diagnosis, guiding selection of therapy, and monitoring interventions. Previously, we determined that plasma of recent-onset (RO) Type 1 diabetes (T1D) patients induce a proinflammatory transcriptional signature in fresh peripheral blood mononuclear cells (PBMC) relative to that of unrelated healthy controls (HC). Here, using an optimized cryopreserved PBMC-based protocol, we analyzed larger RO T1D, HC, and healthy T1D sibling cohorts. In addition, we examined T1D progression by looking at longitudinal samples. UPN727 cells were stimulated with Auto-antibody-negative (AA-) High HLA Risk Siblings plasma (n=30), Auto-antibody-negative (AA-) Low HLA Risk Siblings plasma (n=42), Recent onset T1DM plasma cultured with IL1RA (n=42), or longitudinal series plasma on T1DM progressor (n=27 chips, 5 series), on auto-antibody-positive (AA+) High HLA Risk Siblings (n=54 chips, 9 series), on auto-antibody-negative (AA-) High HLA Risk Siblings (n=60 chips, 12 series), on auto-antibody-negative (AA-) Low HLA Risk Siblings (n=31 chips, 6 series). Gene expression analysis was perfromed in order to evaluate the transcriptional signature associated with T1D.

ORGANISM(S): Homo sapiens

SUBMITTER: Martin Hessner

PROVIDER: E-GEOD-52724 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Molecular signatures differentiate immune states in type 1 diabetic families.

Chen Yi-Guang YG Cabrera Susanne M SM Jia Shuang S Kaldunski Mary L ML Kramer Joanna J Cheong Sami S Geoffrey Rhonda R Roethle Mark F MF Woodliff Jeffrey E JE Greenbaum Carla J CJ Wang Xujing X Hessner Martin J MJ

Diabetes 20140423 11

Mechanisms associated with type 1 diabetes (T1D) development remain incompletely defined. Using a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially interleukin (IL)-1-dependent signatures associated with preonset and recent onset (RO) T1D relative to unrelated healthy control subjects (uHC). To better understand inherited susceptibility in T1D families, we conducted cross-secti ...[more]

PMID: 24760139

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Project description:Both genetic and environmental factors are implicated in Type 1 Diabetes (T1D). Since environmental factors can trigger epigenetic changes, we hypothesized that variations in histone posttranslational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy non-diabetic controls, and explored their connections to T1D. We used the chromatin-immunoprecipitation-linked-to-microarray approach to profile key histone PTMs, including H3-lysine-4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac) and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac and H4K16Ac at the IDDM1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the IDDM1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon- and TNF-treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response towards external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility. We evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy non-diabetic controls, and explored their connections to T1D. We used the ChIP-chip approach to profile key histone PTMs, including histone H3K4me3, H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac) and H4K16Ac, at genes within the T1D susceptible loci in lymphocytes.

Dataset Information

Molecular signatures differentiate immune states in Type 1 Diabetes families

Publications

Molecular signatures differentiate immune states in type 1 diabetic families.

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