Defining the Leukemia Epigenome: Distinct Genome Wide Histone H3 Modification Patterns Exist in AML, ALL and Healthy Hematopoietic Progenitor Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2124-2124
Author(s):  
Carsten Muller-Tidow ◽  
Claudia Homme ◽  
Hans-Ulrich Klein ◽  
Antje Hascher ◽  
Steffen Koschmieder ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Histone Modification ◽  
Progenitor Cells ◽  
Chromatin Modification ◽  
Histone H3 ◽  
Support Vector ◽  
Acute Leukemias ◽  
Histone H3 Acetylation ◽  
H3 Acetylation ◽  
Histone Modification Patterns

Abstract Aberrant transcriptional regulation plays a crucial role in the pathogenesis of acute leukemias. Chromosomal translocations and other mutations frequently affect transcription and chromatin regulation-associated genes in these diseases. Based on these findings we hypothesized that distinct global chromatin modification patterns exist that can distinguish between progenitor cells (CD34+ HSC) and acute leukemia as well as its subtypes. We used high density oligonucleotide ChIP-Chip assays querying more than 31,000 genomic loci to analyze global Histone H3 acetylation (H3Ac) and Lysine 9 (H3K9me3) trimethylation patterns each in a large number of AML (n=115), ALL (n=30), CD34+ HSC (n= 21) and peripheral blood cell (N=18) specimens. Class comparisons and predictions as well as unsupervised analyses were performed. Bioinformatic analyses led to histone modification maps across the genome with Histone H3 acetylation levels peaking around the predicted transcriptional start sites. More than 1000 loci differed in H3 acetylation and H3K9me3 between AML and CD34+ specimens (5% FDR). Among the regulatory classes over-represented among the altered genes were those involved in oncogenesis and cellular proliferation/differentiation. Histone H3 acetylation and H3K9me3 patterns also differed at hundreds of loci between ALL and AML samples (5% FDR). Genes involved in transcriptional regulation were significantly altered between the two leukemia subtypes. Specific differences in global chromatin modifications allowed support vector machine-based classification of CD34+ progenitor cells, AML, and ALL, with about 90% sensitivity and specificity based on Histone H3 acetylation patterns. A similar classification power was observed for H3K9me3. Within the AML patients, several groups of patients were identified that clustered together in unsupervised hierarchical cluster analysis due to similar histone modification patterns. These patterns did not primarily depend on patients′ karyotypes,, indicating that it may be possible to define some, as yet unknown, different types of AML based on chromatin modification. On a global scale, acute leukemias are associated with specific histone modification patterns that distinguish AML from ALL and CD34+ hematopoietic progenitors. Taken together, these first data on the leukemia epigenome provide the basis for improved understanding of genes involved in leukemia pathogenesis.

ChIP-Chip in Primary AML Blasts Identifies Peroxiredoxin-II as An Epigenetically Silenced Tumor Suppressor.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3351-3351
Author(s):  
Shuchi Agrawal-Singh ◽  
Markus Wiechmann ◽  
Sandra Doths ◽  
Christina Nolte ◽  
Nils Heinrich Thoennissen ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Progenitor Cells ◽  
Histone H3 ◽  
U937 Cells ◽  
Oxygen Species ◽  
Dna Hypermethylation ◽  
Tyrosine Kinase Signaling ◽  
Histone H3 Acetylation ◽  
H3 Acetylation ◽  
Chip Chip

Abstract Epigenetic silencing of tumor suppressors is a frequent event in leukemogenesis. We performed ChIP-Chip to identify genes with altered Histone H3 acetylation in primary AML specimens (n=115) and normal CD34+ progenitor cells (n=21). Interestingly, promoters of several members of the peroxiredoxin family (PrdxII and Prdx IV) were identified to be significantly Histone H3 hypoacetylated in primary AML blasts. Peroxiredoxins (Prdx) are antioxidant enzymes that regulate the amount of reactive oxygen species in the cell. Prdx scavenge H2O2 and protect cells from oxidative damage to cellular DNA, lipid and proteins. Confirmation by quantitative PCR revealed that the PrdxII promoter was hypoacetylated in AML, and mRNA expression was 10-fold induced in U937 cells upon exposure to the demethylating agent 5-Azadeoxycytidine (Aza). Demethylation of U937 cells by Aza resulted in increased Histone H3 acetylation at the PrdxII promoter. DNA hypermethylation was frequent in primary AML blasts (18/103) but not in control samples (0/40) as assessed by methylation-specific PCR. Hypoacetylation of Histone H3 and DNA hypermethylation was associated with repression of PrdxII mRNA and protein levels in primary AML samples. Decreased PrdxII protein expression as assessed by immunohistochemistry in a tissue microarray was associated with a poor prognosis in AML patients. On the functional level, PrdxII inhibited the growth of hematopoietic progenitor cells in colony assays and negatively influenced receptor tyrosine kinase signaling by inhibition of ERK and AKT activation upon overexpression. Conversely, PrdxII knock-down by shRNA in myeloid progenitor cell lines and in murine primary bone marrow cells led to enhanced growth and tyrosine kinase signaling. A decrease in PrdxII levels was associated with an increase in reactive oxygen species and enhanced phosphorylation of STAT5, AKT and ERK. Taken together, these findings suggest that chromatin modifications in AML suppress expression of PrdxII. Our data also revealed that PrdxII is a novel putative tumor suppressor in AML.

scholarly journals Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. 2346-2357 ◽  
Author(s):  
Shuchi Agrawal-Singh ◽  
Fabienne Isken ◽  
Konstantin Agelopoulos ◽  
Hans-Ulrich Klein ◽  
Nils H. Thoennissen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Protein Expression ◽  
Progenitor Cells ◽  
Tumor Suppressor Gene ◽  
Core Promoter ◽  
Histone H3 ◽  
Suppressor Gene ◽  
Dna Hypermethylation ◽  
Histone H3 Acetylation ◽  
H3 Acetylation

Abstract With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34+ progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML, which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in patients with AML. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc–induced leukemogenesis in vivo on BM transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML led to the identification of PRDX2 as an epigenetically silenced growth suppressor, suggesting a possible role of ROS in the malignant phenotype in AML.

scholarly journals Butyrate Stimulates Histone H3 Acetylation, 8-Isoprostane Production, RANKL Expression, and Regulated Osteoprotegerin Expression/Secretion in MG-63 Osteoblastic Cells

2018 ◽  
Vol 19 (12) ◽  
pp. 4071 ◽  
Author(s):  
Mei-Chi Chang ◽  
Yunn-Jy Chen ◽  
Yun-Chia Lian ◽  
Bei-En Chang ◽  
Chih-Chia Huang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Viability ◽  
Butyric Acid ◽  
Root Canal ◽  
Histone H3 ◽  
Rankl Expression ◽  
Alp Activity ◽  
Histone H3 Acetylation ◽  
Apoptosis And Necrosis ◽  
H3 Acetylation

Butyric acid as a histone deacetylase (HDAC) inhibitor is produced by a number of periodontal and root canal microorganisms (such as Porphyromonas, Fusobacterium, etc.). Butyric acid may affect the biological activities of periodontal/periapical cells such as osteoblasts, periodontal ligament cells, etc., and thus affect periodontal/periapical tissue destruction and healing. The purposes of this study were to study the toxic effects of butyrate on the matrix and mineralization marker expression in MG-63 osteoblasts. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cellular apoptosis and necrosis were analyzed by propidium iodide/annexin V flow cytometry. The protein and mRNA expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) were analyzed by Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). OPG, soluble RANKL (sRANKL), 8-isoprostane, pro-collagen I, matrix metalloproteinase-2 (MMP-2), osteonectin (SPARC), osteocalcin and osteopontin (OPN) secretion into culture medium were measured by enzyme-linked immunosorbant assay. Alkaline phosphatase (ALP) activity was checked by ALP staining. Histone H3 acetylation levels were evaluated by immunofluorescent staining (IF) and Western blot. We found that butyrate activated the histone H3 acetylation of MG-63 cells. Exposure of MG-63 cells to butyrate partly decreased cell viability with no marked increase in apoptosis and necrosis. Twenty-four hours of exposure to butyrate stimulated RANKL protein expression, whereas it inhibited OPG protein expression. Butyrate also inhibited the secretion of OPG in MG-63 cells, whereas the sRANKL level was below the detection limit. However, 3 days of exposure to butyrate (1 to 8 mM) or other HDAC inhibitors such as phenylbutyrate, valproic acid and trichostatin stimulated OPG secretion. Butyrate stimulated 8-isoprostane, MMP-2 and OPN secretion, but not procollagen I, or osteocalcin in MG-63 cells. Exposure to butyrate (2–4 mM) for 3 days markedly stimulated osteonectin secretion and ALP activity. In conclusion, higher concentrations of butyric acid generated by periodontal and root canal microorganisms may potentially induce bone destruction and impair bone repair by the alteration of OPG/RANKL expression/secretion, 8-isoprostane, MMP-2 and OPN secretion, and affect cell viability. However, lower concentrations of butyrate (1–4 mM) may stimulate ALP, osteonectin and OPG. These effects are possibly related to increased histone acetylation. These events are important in the pathogenesis and repair of periodontal and periapical destruction.

scholarly journals Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation

2011 ◽  
Vol 30 (14) ◽  
pp. 2829-2842 ◽  
Author(s):  
Chuanbing Bian ◽  
Chao Xu ◽  
Jianbin Ruan ◽  
Kenneth K Lee ◽  
Tara L Burke ◽  
...  
Keyword(s):  
Histone H3 ◽  
Saga Complex ◽  
Histone H3 Acetylation ◽  
H3 Acetylation

scholarly journals Promoter-specific changes in initiation, elongation and homeostasis of histone H3 acetylation during CBP/p300 inhibition

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Emily Hsu ◽  
Nathan R Zemke ◽  
Arnold J Berk
Keyword(s):  
Rna Polymerase Ii ◽  
Control Point ◽  
Histone H3 ◽  
Airway Epithelial Cells ◽  
Proximal Region ◽  
Transferase Activity ◽  
Transcriptional Elongation ◽  
Elongation Complex ◽  
Histone H3 Acetylation ◽  
H3 Acetylation

Regulation of RNA Polymerase II (Pol2) elongation in the promoter proximal region is an important and ubiquitous control point for gene expression in metazoans. We report that transcription of the adenovirus 5 E4 region is regulated during the release of paused Pol2 into productive elongation by recruitment of the super elongation complex (SEC), dependent on promoter H3K18/27 acetylation by CBP/p300. We also establish that this is a general transcriptional regulatory mechanism that applies to ~6% of expressed protein-coding genes in primary human airway epithelial cells. We observed that a homeostatic mechanism maintains promoter, but not enhancer H3K18/27ac in response to extensive inhibition of CBP/p300 acetyl transferase activity by the highly specific small molecule inhibitor A-485. Further, our results suggest a function for BRD4 association at enhancers in regulating paused Pol2 release at nearby promoters. Taken together, our results uncover processes regulating transcriptional elongation by promoter region histone H3 acetylation and homeostatic maintenance of promoter, but not enhancer, H3K18/27ac in response to inhibition of CBP/p300 acetyl transferase activity.

scholarly journals Interplay between Chromatin and trans-Acting Factors on the IME2 Promoter upon Induction of the Gene at the Onset of Meiosis

2006 ◽  
Vol 27 (4) ◽  
pp. 1254-1263 ◽  
Author(s):  
Tomomi Inai ◽  
Masashi Yukawa ◽  
Eiko Tsuchiya
Keyword(s):  
Histone Deacetylase ◽  
Chromatin Structure ◽  
Molecular Basis ◽  
Histone Acetyltransferase ◽  
Histone H3 ◽  
Repressive Chromatin ◽  
Tata Element ◽  
Histone H3 Acetylation ◽  
Low Levels ◽  
H3 Acetylation

ABSTRACT The IME2 gene is one of the key regulators of the initiation of meiosis in budding yeast. This gene is repressed during mitosis through the repressive chromatin structure at the promoter, which is maintained by the Rpd3-Sin3 histone deacetylase (HDAC) complex. IME2 expression in meiosis requires Gcn5/histone acetyltransferase, the transcriptional activator Ime1, and the chromatin remodeler RSC; however, the molecular basis of IME2 activation had not been previously defined. We found that, during mitotic growth, a nucleosome masked the TATA element of IME2, and this positioning depended on HDAC. This chromatin structure was remodeled at meiosis by RSC that was recruited to TATA by Ime1. Stable tethering of Ime1 to the promoter required the presence of Gcn5. Interestingly, Ime1 binding to the promoter was kept at low levels during the very early stages in meiosis, even when the levels of Ime1 and histone H3 acetylation at the promoter were at their highest, making a 4- to 6-h delay of the IME2 expression from that of IME1. HDAC was continuously present at the promoter regardless of the transcriptional condition of IME2, and deletion of RPD3 allowed the IME2 expression shortly after the expression of IME1, suggesting that HDAC plays a role in regulating the timing of IME2 expression.

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