scholarly journals Patterns of Maternal Neutrophil Gene Expression at 30 Weeks of Gestation, but Not DNA Methylation, Distinguish Mild from Severe Preeclampsia

2021 ◽  
Vol 22 (23) ◽  
pp. 12876
Author(s):  
Scott W. Walsh ◽  
Marwah Al Dulaimi ◽  
Kellie J. Archer ◽  
Jerome F. Strauss
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Clinical Symptoms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Normal Pregnancy ◽  
Mirror Image ◽  
Neutrophil Activation ◽  
Severe Preeclampsia ◽  
Mild Preeclampsia

Neutrophils are activated and extensively infiltrate blood vessels in preeclamptic women. To identify genes that contribute to neutrophil activation and infiltration, we analyzed the transcriptomes of circulating neutrophils from normal pregnant and preeclamptic women. Neutrophils were collected at 30 weeks’ gestation and RNA and DNA were isolated for RNA sequencing and 5-hydroxy-methylcytosine (5-hmC) sequencing as an index of dynamic changes in neutrophil DNA methylation. Women with normal pregnancy who went on to develop mild preeclampsia at term had the most uniquely expressed genes (697) with 325 gene ontology pathways upregulated, many related to neutrophil activation and function. Women with severe preeclampsia who delivered prematurely had few pathways up- or downregulated. Cluster analysis revealed that gene expression in women with severe preeclampsia was an inverse mirror image of gene expression in normal pregnancy, while gene expression in women who developed mild preeclampsia was remarkably different from both. DNA methylation marks, key regulators of gene expression, are removed by the action of ten-eleven translocation (TET) enzymes, which oxidize 5-methylcytosines (5mCs), resulting in locus-specific reversal of DNA methylation. DNA sequencing for 5-hmC revealed no differences among the three groups. Genome-wide DNA methylation revealed extremely low levels in circulating neutrophils suggesting they are de-methylated. Collectively, these data demonstrate that neutrophil gene expression profiles can distinguish different preeclampsia phenotypes, and in the case of mild preeclampsia, alterations in gene expression occur well before clinical symptoms emerge. These findings serve as a foundation for further evaluation of neutrophil transcriptomes as biomarkers of preeclampsia phenotypes. Changes in DNA methylation in circulating neutrophils do not appear to mediate differential patterns of gene expression in either mild or severe preeclampsia.

scholarly journals Age-related differences in monocyte DNA methylation and immune function in healthy Kenyan adults and children

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Katherine R. Dobbs ◽  
Paula Embury ◽  
Emmily Koech ◽  
Sidney Ogolla ◽  
Stephen Munga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Young Adults ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Innate Immune ◽  
Inflammatory Gene Expression ◽  
Cpg Sites ◽  
Age Related ◽  
Adults And Children

Abstract Background Age-related changes in adaptive and innate immune cells have been associated with a decline in effective immunity and chronic, low-grade inflammation. Epigenetic, transcriptional, and functional changes in monocytes occur with aging, though most studies to date have focused on differences between young adults and the elderly in populations with European ancestry; few data exist regarding changes that occur in circulating monocytes during the first few decades of life or in African populations. We analyzed DNA methylation profiles, cytokine production, and inflammatory gene expression profiles in monocytes from young adults and children from western Kenya. Results We identified several hypo- and hyper-methylated CpG sites in monocytes from Kenyan young adults vs. children that replicated findings in the current literature of differential DNA methylation in monocytes from elderly persons vs. young adults across diverse populations. Differentially methylated CpG sites were also noted in gene regions important to inflammation and innate immune responses. Monocytes from Kenyan young adults vs. children displayed increased production of IL-8, IL-10, and IL-12p70 in response to TLR4 and TLR2/1 stimulation as well as distinct inflammatory gene expression profiles. Conclusions These findings complement previous reports of age-related methylation changes in isolated monocytes and provide novel insights into the role of age-associated changes in innate immune functions.

scholarly journals Identification of Prognostic Markers in Cholangiocarcinoma Using Altered DNA Methylation and Gene Expression Profiles

2020 ◽  
Vol 11 ◽  
Author(s):  
Nitish Kumar Mishra ◽  
Meng Niu ◽  
Siddesh Southekal ◽  
Prachi Bajpai ◽  
Amr Elkholy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Prognostic Markers ◽  
Expression Profiles ◽  
Gene Expression Profiles

scholarly journals Profiles of Local and Systemic Inflammation in the Outcome of Treatment of Human Cutaneous Leishmaniasis Caused by Leishmania (Viannia)

2019 ◽  
Vol 88 (3) ◽  
Author(s):  
Adriana Navas ◽  
Olga Fernández ◽  
Carolina Gallego-Marín ◽  
María del Mar Castro ◽  
Mariana Rosales-Chilama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Treatment Failure ◽  
Cutaneous Leishmaniasis ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Neutrophil Activation ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Biopsy Specimens

ABSTRACT The immune mechanisms that contribute to the efficacy of treatment of cutaneous leishmaniasis (CL) are not fully understood. The aim of this study was to define immune correlates of the outcome of treatment of CL caused by Leishmania (Viannia) species during standard of care treatment with pentavalent antimonials. We conducted a comparative expression profiling of immune response genes in peripheral blood mononuclear cells (PBMCs) and lesion biopsy specimens obtained from CL patients before and at the end of treatment (EoT) with meglumine antimoniate. The ex vivo response of PBMCs to L. (V.) panamensis partially reflected that of lesion microenvironments. Significant downregulation of gene expression profiles consistent with local innate immune responses (monocyte and neutrophil activation and chemoattractant molecules) was observed at EoT in biopsy specimens of patients who cured (n = 8), compared to those from patients with treatment failure (n = 8). Among differentially expressed genes, pretreatment expression of CCL2 was significantly predictive of the therapeutic response (receiver operating characteristic [ROC] curve, area under the curve [AUC] = 0.82, P = 0.02). Polymorphisms in regulatory regions of the CCL2 promoter were analyzed in a pilot cohort of DNA samples from CL patients (cures, n = 20, and treatment failure, n = 20), showing putative association of polymorphisms rs13900(C/T) and rs2857656(G/C) with treatment outcome. Our data indicate that dampening gene expression profiles of monocyte and neutrophil activation characterize clinical cure after treatment of CL, supporting participation of parasite-sustained inflammation or deregulated innate immune responses in treatment failure.

scholarly journals Gene Expression Profiling of the Human Maternal-Fetal Interface Reveals Dramatic Changes between Midgestation and Term

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1059-1079 ◽  
Author(s):  
Virginia D. Winn ◽  
Ronit Haimov-Kochman ◽  
Agnes C. Paquet ◽  
Y. Jean Yang ◽  
M. S. Madhusudhan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Global Analysis ◽  
Tumor Biology ◽  
Gene Expression Profiles ◽  
Normal Pregnancy ◽  
Differentially Expressed ◽  
Basal Plate ◽  
Specialized Region ◽  
Maternal Fetal Interface

Human placentation entails the remarkable integration of fetal and maternal cells into a single functional unit. In the basal plate region (the maternal-fetal interface) of the placenta, fetal cytotrophoblasts from the placenta invade the uterus and remodel the resident vasculature and avoid maternal immune rejection. Knowing the molecular bases for these unique cell-cell interactions is important for understanding how this specialized region functions during normal pregnancy with implications for tumor biology and transplantation immunology. Therefore, we undertook a global analysis of the gene expression profiles at the maternal-fetal interface. Basal plate biopsy specimens were obtained from 36 placentas (14–40 wk) at the conclusion of normal pregnancies. RNA was isolated, processed, and hybridized to HG-U133A&B Affymetrix GeneChips. Surprisingly, there was little change in gene expression during the 14- to 24-wk interval. In contrast, 418 genes were differentially expressed at term (37–40 wk) as compared with midgestation (14–24 wk). Subsequent analyses using quantitative PCR and immunolocalization approaches validated a portion of these results. Many of the differentially expressed genes are known in other contexts to be involved in differentiation, motility, transcription, immunity, angiogenesis, extracellular matrix dissolution, or lipid metabolism. One sixth were nonannotated or encoded hypothetical proteins. Modeling based on structural homology revealed potential functions for 31 of these proteins. These data provide a reference set for understanding the molecular components of the dialogue taking place between maternal and fetal cells in the basal plate as well as for future comparisons of alterations in this region that occur in obstetric complications.

scholarly journals Global Modulation in DNA Epigenetics during Pro-Inflammatory Macrophage Activation

2019 ◽  
Author(s):  
Nikhil Jain ◽  
Tamar Shahal ◽  
Tslil Gabrieli ◽  
Noa Gilat ◽  
Dmitry Torchinsky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Single Molecule ◽  
Transcriptional Control ◽  
Excision Repair ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Inflammatory Activation ◽  
Methylation Patterns

AbstractDNA methylation patterns create distinct gene expression profiles. These patterns are maintained after cell division, thus enabling the differentiation and maintenance of multiple cell types from the same genome sequence. The advantage of this mechanism for transcriptional control is that chemical-encoding allows to rapidly establish new epigenetic patterns “on-demand” through enzymatic methylation and de-methylation of DNA. Here we show that this feature is associated with the fast response of macrophages during their pro-inflammatory activation. By using a combination of mass spectroscopy and single-molecule imaging to quantify global epigenetic changes in the genomes of primary macrophages, we followed three distinct DNA marks (methylated, hydroxymethylated and unmethylated), involved in establishing new DNA methylation patterns during pro-inflammatory activation. The observed epigenetic modulation together with gene expression data generated for the involved enzymatic machinery, may suggest that de-methylation upon LPS-activation starts with oxidation of methylated CpGs, followed by excision-repair of these oxidized bases and their replacement with unmodified cytosine.

scholarly journals Comparison of visceral adipose tissue DNA methylation and gene expression profiles in female adolescents with obesity

2019 ◽  
Author(s):  
Matthew D. Barberio ◽  
Evan P. Nadler ◽  
Samantha Sevilla ◽  
Rosemary Lu ◽  
Brennan Harmon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Akt Signaling ◽  
Adolescent Females ◽  
Akt Signaling Pathway ◽  
Visceral Adipose

AbstractBackgroundEpigenetic changes in visceral adipose tissue (VAT) with obesity and their effects on gene expression are poorly understood, especially during emergent obesity in youth. The current study tested the hypothesis that methylation and gene expression profiles of key growth factor and inflammatory pathways such as PI3K/AKT signaling are altered in VAT from obese compared to non-obese youth.MethodsVAT samples from adolescent females grouped as Lean (L; n=15; age=15±3 yrs, BMI=21.9±3.0 kg/m2) or Obese (Ob; n=15, age=16±2 yrs, BMI=45.8±9.8 kg/m2) were collected. Global methylation (n=20) and gene expression (N=30) patterns were profiled via microarray and interrogated for differences between groups by ANCOVA (p<0.05), followed by biological pathway analysis.ResultsOverlapping differences in methylation and gene expression in 317 genes were found in VAT from obese compared to lean groups. PI3K/AKT Signaling (p=1.83×10−6; 10/121 molecules in dataset/pathway) was significantly overrepresented in Ob VAT according to pathway analysis. mRNA upregulations in the PI3K/AKT Signaling Pathway genes TFAM (p=0.03; Fold change=1.8) and PPP2R5C (p=0.03, FC=2.6) were confirmed via qRT-PCR.ConclusionOur analyses show obesity-related differences in DNA methylation and gene expression in visceral adipose tissue of adolescent females. Specifically, we identified methylation site/gene expression pairs differentially regulated and mapped these differences to PI3K/AKT signaling, suggesting that PI3K/AKT signaling pathway dysfunction in obesity may be driven in part by obesity-related changes in DNA methylation.

scholarly journals Transcriptional profiling enables molecular classification of adrenocortical tumours

2009 ◽  
Vol 161 (1) ◽  
pp. 141-152 ◽  
Author(s):  
Cecilia Laurell ◽  
David Velázquez-Fernández ◽  
Kristina Lindsten ◽  
Christofer Juhlin ◽  
Ulla Enberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Symptoms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Differentially Expressed ◽  
Molecular Signature ◽  
Survival Prediction ◽  
Cdna Clones ◽  
Hormonal Activity ◽  
Adrenocortical Tumours

ObjectiveTumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5–2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities.MethodsMicroarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis.ResultsUnsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples.ConclusionsAdrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.

302. FIBROID ASSOCIATED HEAVY MENSTRUAL BLEEDING: CORRELATION OF CLINICAL SYMPTOMS, DOPPLER ULTRASOUND ASSESSMENT OF VASCULATURE AND TISSUE GENE EXPRESSION PROFILES

2010 ◽  
Vol 22 (9) ◽  
pp. 102
Author(s):  
S. Tsiligiannis ◽  
M. Zaitseva ◽  
P. Coombs ◽  
P. Shekleton ◽  
B. Vollenhoven ◽  
...  
Keyword(s):  
Gene Expression ◽  
Doppler Ultrasound ◽  
Clinical Symptoms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Heavy Menstrual Bleeding ◽  
Spectral Doppler ◽  
Ultrasound Assessment ◽  
Angiogenic Gene ◽  
Tissue Gene Expression

Understanding of the mechanisms that cause fibroid associated heavy menstrual bleeding (HMB) is limited. Despite many fibroids having a highly vascular peri-fibroid myometrial (PFM) zone, angiogenic gene expression in this area has never been investigated. The aim of this study was to correlate clinical symptoms, ultrasound appearances and tissue gene expression profiles in women scheduled for hysterectomy due to symptomatic fibroids. We hypothesised that fibroid heterogeneity, colour flow and spectral Doppler resistive indices would correlate with differences in gene expression profiles. It was thought and that increased peri-fibroid gene expression of key angiogenic genes would correlate with increased peri-fibroid vascularity. N = 6 patients underwent B-mode, colour and spectral Doppler ultrasound assessment. Following hysterectomy tissue samples collected from three areas – fibroid, PFM and distant myometrium (DM) were analysed using quantitative RT-PCR and a customised angiogenesis PCR array. A higher mean peak systolic velocity (PSV) in the PFM region when compared to mean PSV within the fibroid (P < 0.001) was seen. Differences in angiogenic gene expression were consistent with the heterogeneity of the clinical data collected. One fibroid sample showed dissimilar gene expression to all other fibroids; at ultrasound and sample collection significant degenerative features were observed. Fibroid heterogeneity within a single uterus was also demonstrated, with two fibroids from the one uterus having significantly dissimilar gene profiles and ultrasound appearances. No differences in gene expression were found between PFM and DM. Despite this, gene interaction maps showed different interaction of genes between fibroid and PFM regions compared to genes between the fibroid and the DM. These are the first molecular data demonstrating that the PFM region may be functionally distinct from distant myometrium.

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