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Article ; Online: The normalization of gene expression data in melanoma: investigating the use of glyceraldehyde 3-phosphate dehydrogenase and 18S ribosomal RNA as internal reference genes for quantitative real-time PCR.

Giricz, Orsolya / Lauer-Fields, Janelle L / Fields, Gregg B

2008 Volume 380, Issue 1, Page(s) 137–139

Abstract: We examined a panel of 26 melanoma and fibroblast samples (tissues and cultured cells) to evaluate the suitability of two commonly used housekeeping genes, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 18S ribosomal RNA (rRNA), for quantitative ... ...

Abstract	We examined a panel of 26 melanoma and fibroblast samples (tissues and cultured cells) to evaluate the suitability of two commonly used housekeeping genes, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 18S ribosomal RNA (rRNA), for quantitative real-time PCR. Both genes showed significant variations within the individual cell line and tissue groups. Although no overall trends were observed in the expression of the 18S rRNA, GAPDH was up-regulated in melanoma tissue and cultured cells compared with the corresponding normal samples. In melanoma and fibroblast cell lines and tissues, absolute quantification appears to be more appropriate than normalizing messenger RNA (mRNA) expression via GAPDH or 18S rRNA housekeeping genes.
MeSH term(s)	Cell Line, Tumor ; Gene Expression Profiling/standards ; Gene Expression Regulation, Neoplastic ; Glyceraldehyde-3-Phosphate Dehydrogenases/genetics ; Humans ; Melanoma/genetics ; Polymerase Chain Reaction/methods ; RNA, Messenger/genetics ; RNA, Ribosomal, 18S/genetics ; Reference Standards ; Time Factors
Chemical Substances	RNA, Messenger ; RNA, Ribosomal, 18S ; Glyceraldehyde-3-Phosphate Dehydrogenases (EC 1.2.1.-)
Language	English
Publishing date	2008-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1110-1
ISSN	1096-0309 ; 0003-2697
ISSN (online)	1096-0309
ISSN	0003-2697
DOI	10.1016/j.ab.2008.05.024
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Article ; Online: Targeting chemokine pathways in esophageal adenocarcinoma.

Shrivastava, Makardhwaj S / Hussain, Zulfiqar / Giricz, Orsolya / Shenoy, Niraj / Polineni, Rahul / Maitra, Anirban / Verma, Amit

Cell cycle (Georgetown, Tex.)

2014 Volume 13, Issue 21, Page(s) 3320–3327

Abstract: Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US and needs newer therapeutic and diagnostic strategies. Chronic inflammation plays a role in the pathogenesis of EAC and contributes to the dysplastic conversion of ... ...

Abstract	Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US and needs newer therapeutic and diagnostic strategies. Chronic inflammation plays a role in the pathogenesis of EAC and contributes to the dysplastic conversion of normal esophageal epithelium to Barrett's esophagus and frank adenocarcinoma. Chemokines play important roles in mediating inflammation and recent evidence implicates these ligands and their receptors in the development and spread of various tumors. We demonstrated that the chemokines IL8, CXCL1 and CXCL3 are significantly overexpressed during esophageal carcinogenesis and accompanied by amplification and demethylation of the chr4q21 gene locus. We also demonstrated that IL8 levels can be detected in serum of patients with EAC and can serve as potential biomarkers. We now demonstrate that inhibition of IL8 receptor, CXCR2, leads to decreased invasiveness of esophageal adenocarcinoma derived cells without affecting cellular proliferation. Taken together, these studies reveal the important roles that chemokines play in development of esophageal cancer and demonstrate that these pathways can serve as potential therapeutic targets.
MeSH term(s)	Adenocarcinoma/metabolism ; Adenocarcinoma/pathology ; Barrett Esophagus/metabolism ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; Cell Movement ; Cell Survival ; Chemokine CXCL1/metabolism ; Chemokines, CXC/metabolism ; Esophageal Neoplasms/metabolism ; Esophageal Neoplasms/pathology ; Humans ; Interleukin-8/blood ; Interleukin-8/metabolism ; Neoplasm Metastasis ; Neovascularization, Pathologic ; Receptors, Interleukin-8/antagonists & inhibitors ; Receptors, Interleukin-8/metabolism ; Receptors, Interleukin-8B/antagonists & inhibitors ; Receptors, Interleukin-8B/metabolism
Chemical Substances	Biomarkers, Tumor ; CXCL3 protein, human ; Chemokine CXCL1 ; Chemokines, CXC ; Interleukin-8 ; Receptors, Interleukin-8 ; Receptors, Interleukin-8B
Language	English
Publishing date	2014-12-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/15384101.2014.968426
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Zs.A 5881: Show issues

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Article ; Online: Multiple Myeloma and Its Precursor Disease Among Firefighters Exposed to the World Trade Center Disaster.

JAMA oncology

2018 Volume 4, Issue 6, Page(s) 821–827

Abstract: Importance: The World Trade Center (WTC) attacks on September 11, 2001, created an unprecedented environmental exposure to known and suspected carcinogens suggested to increase the risk of multiple myeloma. Multiple myeloma is consistently preceded by ... ...

Abstract	Importance: The World Trade Center (WTC) attacks on September 11, 2001, created an unprecedented environmental exposure to known and suspected carcinogens suggested to increase the risk of multiple myeloma. Multiple myeloma is consistently preceded by the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS, detectable in peripheral blood. Objective: To characterize WTC-exposed firefighters with a diagnosis of multiple myeloma and to conduct a screening study for MGUS and light-chain MGUS. Design, setting, and participants: Case series of multiple myeloma in firefighters diagnosed between September 11, 2001, and July 1, 2017, together with a seroprevalence study of MGUS in serum samples collected from Fire Department of the City of New York (FDNY) firefighters between December 2013 and October 2015. Participants included all WTC-exposed FDNY white, male firefighters with a confirmed physician diagnosis of multiple myeloma (n = 16) and WTC-exposed FDNY white male firefighters older than 50 years with available serum samples (n = 781). Exposures: WTC exposure defined as rescue and/or recovery work at the WTC site between September 11, 2001, and July 25, 2002. Main outcomes and measures: Multiple myeloma case information, and age-adjusted and age-specific prevalence rates for overall MGUS (ie, MGUS and light-chain MGUS), MGUS, and light-chain MGUS. Results: Sixteen WTC-exposed white male firefighters received a diagnosis of multiple myeloma after September 11, 2001; median age at diagnosis was 57 years (interquartile range, 50-68 years). Serum/urine monoclonal protein isotype/free light-chain data were available for 14 cases; 7 (50%) had light-chain multiple myeloma. In a subset of 7 patients, myeloma cells were assessed for CD20 expression; 5 (71%) were CD20 positive. In the screening study, we assayed peripheral blood from 781 WTC-exposed firefighters. The age-standardized prevalence rate of MGUS and light-chain MGUS combined was 7.63 per 100 persons (95% CI, 5.45-9.81), 1.8-fold higher than rates from the Olmsted County, Minnesota, white male reference population (relative rate, 1.76; 95% CI, 1.34-2.29). The age-standardized prevalence rate of light-chain MGUS was more than 3-fold higher than in the same reference population (relative rate, 3.13; 95% CI, 1.99-4.93). Conclusions and relevance: Environmental exposure to the WTC disaster site is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype.
MeSH term(s)	Adult ; Age Distribution ; Age of Onset ; Aged ; Air Pollutants/adverse effects ; Antigens, CD20/analysis ; Disasters ; Environmental Restoration and Remediation ; Firefighters ; Humans ; Immunoglobulin Light Chains/blood ; Immunoglobulin Light Chains/urine ; Male ; Middle Aged ; Minnesota/epidemiology ; Monoclonal Gammopathy of Undetermined Significance/blood ; Monoclonal Gammopathy of Undetermined Significance/epidemiology ; Monoclonal Gammopathy of Undetermined Significance/etiology ; Monoclonal Gammopathy of Undetermined Significance/urine ; Multiple Myeloma/blood ; Multiple Myeloma/epidemiology ; Multiple Myeloma/etiology ; Myeloma Proteins/analysis ; New York City/epidemiology ; Prevalence ; Rescue Work ; Risk Factors ; September 11 Terrorist Attacks
Chemical Substances	Air Pollutants ; Antigens, CD20 ; Immunoglobulin Light Chains ; Myeloma Proteins
Language	English
Publishing date	2018-05-09
Publishing country	United States
Document type	Journal Article
ISSN	2374-2445
ISSN (online)	2374-2445
DOI	10.1001/jamaoncol.2018.0509
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Article ; Online: IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.

Schinke, Carolina / Giricz, Orsolya / Li, Weijuan / Shastri, Aditi / Gordon, Shanisha / Barreyro, Laura / Barreryo, Laura / Bhagat, Tushar / Bhattacharyya, Sanchari / Ramachandra, Nandini / Bartenstein, Matthias / Pellagatti, Andrea / Boultwood, Jacqueline / Wickrema, Amittha / Yu, Yiting / Will, Britta / Wei, Sheng / Steidl, Ulrich / Verma, Amit

Blood

2015 Volume 125, Issue 20, Page(s) 3144–3152

Abstract: Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for ... ...

Abstract	Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival/drug effects ; Cluster Analysis ; Disease Models, Animal ; Gene Expression ; Gene Expression Profiling ; Hematopoietic Stem Cells/metabolism ; Humans ; Interleukin-8/genetics ; Interleukin-8/metabolism ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/mortality ; Mice ; Myelodysplastic Syndromes/drug therapy ; Myelodysplastic Syndromes/genetics ; Myelodysplastic Syndromes/metabolism ; Myelodysplastic Syndromes/mortality ; Neoplastic Stem Cells/metabolism ; Prognosis ; Receptors, Interleukin-8B/antagonists & inhibitors ; Receptors, Interleukin-8B/metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Interleukin-8 ; Receptors, Interleukin-8B
Language	English
Publishing date	2015-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2015-01-621631
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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Article ; Online: Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells.

Shastri, Aditi / Choudhary, Gaurav / Teixeira, Margarida / Gordon-Mitchell, Shanisha / Ramachandra, Nandini / Bernard, Lumie / Bhattacharyya, Sanchari / Lopez, Robert / Pradhan, Kith / Giricz, Orsolya / Ravipati, Goutham / Wong, Li-Fan / Cole, Sally / Bhagat, Tushar D / Feld, Jonathan / Dhar, Yosman / Bartenstein, Matthias / Thiruthuvanathan, Victor J / Wickrema, Amittha /

Ye, B Hilda / Frank, David A / Pellagatti, Andrea / Boultwood, Jacqueline / Zhou, Tianyuan / Kim, Youngsoo / MacLeod, A Robert / Epling-Burnette, P K / Ye, Minwei / McCoon, Patricia / Woessner, Richard / Steidl, Ulrich / Will, Britta / Verma, Amit

The Journal of clinical investigation

2018 Volume 128, Issue 12, Page(s) 5479–5488

Abstract: Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Transcriptomic analysis of stem and progenitor populations in MDS and AML demonstrated ... ...

Abstract	Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Transcriptomic analysis of stem and progenitor populations in MDS and AML demonstrated overexpression of STAT3 that was validated in an independent cohort. STAT3 overexpression was predictive of a shorter survival and worse clinical features in a large MDS cohort. High STAT3 expression signature in MDS CD34+ cells was similar to known preleukemic gene signatures. Functionally, STAT3 inhibition by a clinical, antisense oligonucleotide, AZD9150, led to reduced viability and increased apoptosis in leukemic cell lines. AZD9150 was rapidly incorporated by primary MDS/AML stem and progenitor cells and led to increased hematopoietic differentiation. STAT3 knockdown also impaired leukemic growth in vivo and led to decreased expression of MCL1 and other oncogenic genes in malignant cells. These studies demonstrate that STAT3 is an adverse prognostic factor in MDS/AML and provide a preclinical rationale for studies using AZD9150 in these diseases.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/genetics ; Female ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Male ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Myelodysplastic Syndromes/drug therapy ; Myelodysplastic Syndromes/genetics ; Myelodysplastic Syndromes/metabolism ; Myelodysplastic Syndromes/pathology ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Oligonucleotides/pharmacology ; STAT3 Transcription Factor/antagonists & inhibitors ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	Neoplasm Proteins ; Oligonucleotides ; STAT3 Transcription Factor ; STAT3 protein, human ; danvatirsen (31N550RD05)
Language	English
Publishing date	2018-11-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI120156
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Article ; Online: Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival.

Hu, Caroline Y / Mohtat, Davoud / Yu, Yiting / Ko, Yi-An / Shenoy, Niraj / Bhattacharya, Sanchari / Izquierdo, Maria C / Park, Ae Seo Deok / Giricz, Orsolya / Vallumsetla, Nishanth / Gundabolu, Krishna / Ware, Kristin / Bhagat, Tushar D / Suzuki, Masako / Pullman, James / Liu, X Shirley / Greally, John M / Susztak, Katalin / Verma, Amit

Clinical cancer research : an official journal of the American Association for Cancer Research

2014 Volume 20, Issue 16, Page(s) 4349–4360

Abstract: Purpose: Even though recent studies have shown that genetic changes at enhancers can influence carcinogenesis, most methylomic studies have focused on changes at promoters. We used renal cell carcinoma (RCC), an incurable malignancy associated with ... ...

Abstract	Purpose: Even though recent studies have shown that genetic changes at enhancers can influence carcinogenesis, most methylomic studies have focused on changes at promoters. We used renal cell carcinoma (RCC), an incurable malignancy associated with mutations in epigenetic regulators, as a model to study genome-wide patterns of DNA methylation at a high resolution. Experimental design: Analysis of cytosine methylation status of 1.3 million CpGs was determined by the HELP assay in RCC and healthy microdissected renal tubular controls. Results: We observed that the RCC samples were characterized by widespread hypermethylation that preferentially affected gene bodies. Aberrant methylation was particularly enriched in kidney-specific enhancer regions associated with H3K4Me1 marks. Various important underexpressed genes, such as SMAD6, were associated with aberrantly methylated, intronic enhancers, and these changes were validated in an independent cohort. MOTIF analysis of aberrantly hypermethylated regions revealed enrichment for binding sites of AP2a, AHR, HAIRY, ARNT, and HIF1 transcription factors, reflecting contributions of dysregulated hypoxia signaling pathways in RCC. The functional importance of this aberrant hypermethylation was demonstrated by selective sensitivity of RCC cells to low levels of decitabine. Most importantly, methylation of enhancers was predictive of adverse prognosis in 405 cases of RCC in multivariate analysis. In addition, parallel copy-number analysis from MspI representations demonstrated novel copy-number variations that were validated in an independent cohort of patients. Conclusions: Our study is the first high-resolution methylome analysis of RCC, demonstrates that many kidney-specific enhancers are targeted by aberrant hypermethylation, and reveals the prognostic importance of these epigenetic changes in an independent cohort.
MeSH term(s)	Biomarkers, Tumor/genetics ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/mortality ; Case-Control Studies ; Cells, Cultured ; Cohort Studies ; DNA Methylation ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Kidney Neoplasms/genetics ; Kidney Neoplasms/mortality ; Organ Specificity ; Prognosis ; Promoter Regions, Genetic ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Survival Rate
Chemical Substances	Biomarkers, Tumor ; RNA, Messenger
Language	English
Publishing date	2014-06-10
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-14-0494
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Article ; Online: Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer.

Bhagat, Tushar D / Zou, Yiyu / Huang, Shizheng / Park, Jihwan / Palmer, Matthew B / Hu, Caroline / Li, Weijuan / Shenoy, Niraj / Giricz, Orsolya / Choudhary, Gaurav / Yu, Yiting / Ko, Yi-An / Izquierdo, María C / Park, Ae Seo Deok / Vallumsetla, Nishanth / Laurence, Remi / Lopez, Robert / Suzuki, Masako / Pullman, James /

Kaner, Justin / Gartrell, Benjamin / Hakimi, A Ari / Greally, John M / Patel, Bharvin / Benhadji, Karim / Pradhan, Kith / Verma, Amit / Susztak, Katalin

The Journal of biological chemistry

2016 Volume 292, Issue 3, Page(s) 837–846

Abstract: Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and ... ...

Abstract	Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq data set also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival. Parallel DNA methylation and copy number analysis demonstrated that both genetic and epigenetic alterations led to NOTCH pathway activation in CCRCC. NOTCH ligand JAGGED1 was overexpressed and associated with loss of CpG methylation of H3K4me1-associated enhancer regions. JAGGED2 was also overexpressed and associated with gene amplification in distinct CCRCC samples. Transgenic expression of intracellular NOTCH1 in mice with tubule-specific deletion of VHL led to dysplastic hyperproliferation of tubular epithelial cells, confirming the procarcinogenic role of NOTCH in vivo Alteration of cell cycle pathways was seen in murine renal tubular cells with NOTCH overexpression, and molecular similarity to human tumors was observed, demonstrating that human CCRCC recapitulates features and gene expression changes observed in mice with transgenic overexpression of the Notch intracellular domain. Treatment with the γ-secretase inhibitor LY3039478 led to inhibition of CCRCC cells in vitro and in vivo In summary, these data reveal the mechanistic basis of NOTCH pathway activation in CCRCC and demonstrate this pathway to a potential therapeutic target.
MeSH term(s)	Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Animals ; Carcinoma, Renal Cell ; CpG Islands ; DNA Methylation ; DNA, Neoplasm/genetics ; DNA, Neoplasm/metabolism ; Female ; Humans ; Jagged-1 Protein/genetics ; Jagged-1 Protein/metabolism ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/genetics ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Male ; Mice ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Protease Inhibitors/pharmacology ; Receptor, Notch1/genetics ; Receptor, Notch1/metabolism ; Signal Transduction
Chemical Substances	DNA, Neoplasm ; JAG1 protein, human ; Jagged-1 Protein ; NOTCH1 protein, human ; Neoplasm Proteins ; Notch1 protein, mouse ; Protease Inhibitors ; Receptor, Notch1 ; Amyloid Precursor Protein Secretases (EC 3.4.-)
Language	English
Publishing date	2016-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.745208
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Article ; Online: High resolution methylome analysis reveals widespread functional hypomethylation during adult human erythropoiesis.

The Journal of biological chemistry

2013 Volume 288, Issue 13, Page(s) 8805–8814

Abstract: Differentiation of hematopoietic stem cells to red cells requires coordinated expression of numerous erythroid genes and is characterized by nuclear condensation and extrusion during terminal development. To understand the regulatory mechanisms governing ...

Abstract	Differentiation of hematopoietic stem cells to red cells requires coordinated expression of numerous erythroid genes and is characterized by nuclear condensation and extrusion during terminal development. To understand the regulatory mechanisms governing these widespread phenotypic changes, we conducted a high resolution methylomic and transcriptomic analysis of six major stages of human erythroid differentiation. We observed widespread epigenetic differences between early and late stages of erythropoiesis with progressive loss of methylation being the dominant change during differentiation. Gene bodies, intergenic regions, and CpG shores were preferentially demethylated during erythropoiesis. Epigenetic changes at transcription factor binding sites correlated significantly with changes in gene expression and were enriched for binding motifs for SCL, MYB, GATA, and other factors not previously implicated in erythropoiesis. Demethylation at gene promoters was associated with increased expression of genes, whereas epigenetic changes at gene bodies correlated inversely with gene expression. Important gene networks encoding erythrocyte membrane proteins, surface receptors, and heme synthesis proteins were found to be regulated by DNA methylation. Furthermore, integrative analysis enabled us to identify novel, potential regulatory areas of the genome as evident by epigenetic changes in a predicted PU.1 binding site in intron 1 of the GATA1 gene. This intronic site was found to be conserved across species and was validated to be a novel PU.1 binding site by quantitative ChIP in erythroid cells. Altogether, our study provides a comprehensive analysis of methylomic and transcriptomic changes during erythroid differentiation and demonstrates that human terminal erythropoiesis is surprisingly associated with hypomethylation of the genome.
MeSH term(s)	Antigens, CD34/biosynthesis ; Binding Sites ; Cell Differentiation ; CpG Islands ; DNA Methylation ; Epigenesis, Genetic ; Epigenomics ; Erythrocytes/cytology ; Erythropoiesis/physiology ; Flow Cytometry/methods ; Gene Expression Profiling ; Gene Expression Regulation ; Genome, Human ; Genomics ; Humans ; Introns ; Methylation ; Oligonucleotide Array Sequence Analysis ; Stem Cells/chemistry
Chemical Substances	Antigens, CD34
Language	English
Publishing date	2013-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.423756
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