Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting

2019 ◽  
Vol 78 (4) ◽  
pp. 529-538 ◽  
Author(s):  
Maarten van der Kroef ◽  
Monica Castellucci ◽  
Michal Mokry ◽  
Marta Cossu ◽  
Marianna Garonzi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Chromatin Immunoprecipitation ◽  
Transcription Start ◽  
Histone Marks ◽  
Transcription Start Sites ◽  
Altered Gene Expression ◽  
Bromodomain Proteins ◽  
Altered Gene

Background and objectiveSystemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes.MethodsChromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression.Results1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression.ConclusionSSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.

Microarray Analysis of Altered Gene Expression and the Role of ATF3 in HK-2 Cells Treated with Hemin

Renal Failure ◽  
2013 ◽  
Vol 35 (5) ◽  
pp. 624-632
Author(s):  
Jingwen Wang ◽  
Dewen Wang ◽  
Yang Li ◽  
Yabing Gao ◽  
Shaoxia Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microarray Analysis ◽  
Altered Gene Expression ◽  
Altered Gene

ChIP-on-Chip Analysis Identified HLXB9 as a Transcription Factor In Hematopoietic Cells and Alters the Expression of Genes Involved In Cell-Adhesion

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2486-2486
Author(s):  
Sarah Wildenhain ◽  
Christian Ruckert ◽  
Svenja Daschkey ◽  
Martin Dugas ◽  
Julia Hauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Adhesion ◽  
Hematopoietic Cells ◽  
Promoter Regions ◽  
Altered Gene Expression ◽  
Altered Gene ◽  
On Chip ◽  
Chip Analysis

Abstract Abstract 2486 Infants with t (7;12)/HLXB9-TEL positive Acute Myeloid Leukemia (AML) have an Event-Free Survival (EFS) of 0 % and are characterized by concomitant HLXB9 (MNX1) expression. However, the role of the homeobox protein HLXB9 on hematopoietic cell development remains unknown. Expression profiling of t (7;12) and t (11;X) positive leukemias revealed up-regulation of cell-cell interacting genes in t (7;12) positive leukemia (Wildenhain et al., 2010). Furthermore, no increased expression of HOX-Genes, like HOXA9 and MEIS1, could be observed in t (7;12) positive leukemia compared to t (11;X) positive leukemia. Based on the altered gene expression profile in t (7;12) positive leukemia we investigated the role of HLXB9 as a transcription factor in hematopoietic cells using ChIP-on-chip analysis and its impact on the cellular gene expression pattern using Affymetrix expression arrays. The myeloid cell line HL60 was stable transfected with a CMV-HLXB9 (HL60/HLXB9) expression vector or an empty vector control (HL60/control). Microarray analysis was performed using “Human Gene 1.0 ST Arrays” (Affymetrix) and data from the HL60/HLXB9 cells were normalized to HL60/control cells. ChIP-on-chip analysis was performed using the “SimpleChIP Enzymatic Chromatin IP Kit” (Cell Signaling Technologies). Hybridisation on “385K RefSeq Promoter arrays” and analysis of raw data were performed by NimbleGen using the NimbleScan software. Data were visualized with the SignalMap software. Altered expression analyses as well as enrichment of promoter regions were validated by quantitative RT-PCR. Expression analysis revealed 81 differentially expressed genes, whereof 63 were down-regulated indicating that HLXB9 acts as a transcriptional repressor, as characteristic for homeobox proteins. CLEC5A, normally expressed in mature myeloid cells, is the highest differentially repressed gene. Further, we identified several differentially expressed genes which interfere in cell-adhesion and/or angiogenesis (e.g. IL8, ZYX, SELL, SPP1, EMILIN2). Western blot analysis of nuclear extracts confirmed the translocation of HLXB9 into the nucleus. ChIP-on-chip analysis revealed binding of HLXB9 to several promoter regions, among them the promoters of ZYX and IL8. Binding of HLXB9 to those promoters results in a decreased gene expression.These data strengthens the hypothesis, that HLXB9 plays a major role in cell adhesion and/or cell interactions. Further we observed increased expression of the adhesion molecule CD11b, when culturing HL60/HLXB9 cells in All-Trans Retinoic Acid (ATRA) containing medium in contrast to HL60/control cells. In summary, this study shows that HLXB9 acts as a transcription factor in hematopoietic cells and has a repressive function on gene expression. HLXB9 target genes regulate cell-adhesion and angiogenesis. This study provides the first molecular results of HLXB9 function in hematopoietic cells and supports the previously published data showing the importance on altered gene expression of cell-cell interacting genes in the pathogenesis of t (7;12) positive leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Altered gene expression patterns in muscle ring finger 1 null mice during denervation- and dexamethasone-induced muscle atrophy

2013 ◽  
Vol 45 (23) ◽  
pp. 1168-1185 ◽  
Author(s):  
J. David Furlow ◽  
Monica L. Watson ◽  
David S. Waddell ◽  
Eric S. Neff ◽  
Leslie M. Baehr ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscle Atrophy ◽  
Intracellular Signaling ◽  
Expression Patterns ◽  
Ring Finger ◽  
Altered Gene Expression ◽  
Catabolic State ◽  
Altered Gene ◽  
Multiple Conditions

Muscle atrophy can result from inactivity or unloading on one hand or the induction of a catabolic state on the other. Muscle-specific ring finger 1 (MuRF1), a member of the tripartite motif family of E3 ubiquitin ligases, is an essential mediator of multiple conditions inducing muscle atrophy. While most studies have focused on the role of MuRF1 in protein degradation, the protein may have other roles in regulating skeletal muscle mass and metabolism. We therefore systematically evaluated the effect of MuRF1 on gene expression during denervation and dexamethasone-induced atrophy. We find that the lack of MuRF1 leads to few differences in control animals, but there were several significant differences in specific sets of genes upon denervation- and dexamethasone-induced atrophy. For example, during denervation, MuRF1 knockout mice showed delayed repression of metabolic and structural genes and blunted induction of genes associated with the neuromuscular junction. In the latter case, this pattern correlates with blunted HDAC4 and myogenin upregulation. Lack of MuRF1 caused fewer changes in the dexamethasone-induced atrophy program, but certain genes involved in fat metabolism and intracellular signaling were affected. Our results demonstrate a new role for MuRF1 in influencing gene expression in two important models of muscle atrophy.

scholarly journals Putative positive role of inflammatory genes in fat deposition supported by altered gene expression in purified human adipocytes and preadipocytes from lean and obese adipose tissues

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Sang-Hyeop Lee ◽  
Nak-Hyeon Choi ◽  
In-Uk Koh ◽  
Bong-Jo Kim ◽  
Song Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Low Grade ◽  
Positive Role ◽  
Inflammatory Genes ◽  
Altered Gene Expression ◽  
Tnf Α ◽  
Altered Gene ◽  
Geo Database

Abstract Background Obesity is a chronic low-grade inflammatory disease that is generally characterized by enhanced inflammation in obese adipose tissue (AT). Here, we investigated alterations in gene expression between lean and obese conditions using mRNA-Seq data derived from human purified adipocytes (ACs) and preadipocytes (preACs). Results Total mRNA-seq data were generated with 27 AC and 21 preAC samples purified from human visceral AT collected during resection surgery in cancer patients, where the samples were classified into lean and obese categories by BMI > 25 kg/m2. We defined four classes of differentially expressed genes (DEGs) by comparing gene expression between (1) lean and obese ACs, (2) lean and obese preACs, (3) lean ACs and lean preACs, and 4) obese ACs and obese preACs. Based on an analysis of comparison 1, numerous canonical obesity-related genes, particularly inflammatory genes including IL-6, TNF-α and IL-1β, i.e., the genes that are expected to be upregulated in obesity conditions, were found to be expressed at significantly lower levels in obese ACs than in lean ACs. In contrast, some inflammatory genes were found to be expressed at higher levels in obese preACs than lean preACs in the analysis of comparison 2. The analysis of comparisons 3 and 4 showed that inflammatory gene classes were expressed at higher levels in differentiated ACs than undifferentiated preACs under both lean and obese conditions; however, the degree of upregulation was significantly greater for lean than for obese conditions. We validated our observations using previously published microarray transcriptome data deposited in the GEO database (GSE80654). Conclusions Taken together, our analyses suggest that inflammatory genes are expressed at lower levels in obese ACs than in lean ACs because lean adipogenesis involves even greater enhancement of inflammatory responses than does obese adipogenesis.

Altered gene expression patterns in intrauterine growth restriction: Potential role of hypoxia

2007 ◽  
Vol 196 (1) ◽  
pp. 70.e1-70.e6 ◽  
Author(s):  
Cathal McCarthy ◽  
Finbarr E. Cotter ◽  
Suzanne McElwaine ◽  
Anne Twomey ◽  
Eoghan E. Mooney ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intrauterine Growth Restriction ◽  
Potential Role ◽  
Expression Patterns ◽  
Growth Restriction ◽  
Gene Expression Patterns ◽  
Intrauterine Growth ◽  
Altered Gene Expression ◽  
Altered Gene

scholarly journals Altered gene expression in cultured microglia in response to simulated blast overpressure: Possible role of pulse duration

2012 ◽  
Vol 522 (1) ◽  
pp. 47-51 ◽  
Author(s):  
Michael J. Kane ◽  
Mariana Angoa-Pérez ◽  
Dina M. Francescutti ◽  
Catherine E. Sykes ◽  
Denise I. Briggs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulse Duration ◽  
Altered Gene Expression ◽  
Blast Overpressure ◽  
Altered Gene
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