Displaying publications 1 - 20 of 39 in total

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  1. Fulltext ING2 (inhibitor of growth protein-2) plays a crucial role in preimplantation development
    Zhou L, Wang P, Zhang J, Heng BC, Tong GQ
    Zygote, 2016 Feb;24(1):89-97.
    PMID: 25672483 DOI: 10.1017/S0967199414000768
    ING2 (inhibitor of growth protein-2) is a member of the ING-gene family and participates in diverse cellular processes involving tumor suppression, DNA repair, cell cycle regulation, and cellular senescence. As a subunit of the Sin3 histone deacetylase complex co-repressor complex, ING2 binds to H3K4me3 to regulate chromatin modification and gene expression. Additionally, ING2 recruits histone methyltransferase (HMT) activity for gene repression, which is independent of the HDAC class I or II pathway. However, the physiological function of ING2 in mouse preimplantation embryo development has not yet been characterized previously. The expression, localization and function of ING2 during preimplantation development were investigated in this study. We showed increasing expression of ING2 within the nucleus from the 4-cell embryo stage onwards; and that down-regulation of ING2 expression by endoribonuclease-prepared small interfering RNA (esiRNA) microinjection results in developmental arrest during the morula to blastocyst transition. Embryonic cells microinjected with ING2-specific esiRNA exhibited decreased blastulation rate compared to the negative control. Further investigation of the underlying mechanism indicated that down-regulation of ING2 significantly increased expression of p21, whilst decreasing expression of HDAC1. These results suggest that ING2 may play a crucial role in the process of preimplantation embryo development through chromatin regulation.
    Matched MeSH terms: Chromatin/genetics; Chromatin/metabolism
  2. TRAIL-based tumor sensitizing galactoxyloglucan, a novel entity for targeting apoptotic machinery
    Aravind SR, Joseph MM, George SK, Dileep KV, Varghese S, Rose-James A, et al.
    Int J Biochem Cell Biol, 2015 Feb;59:153-66.
    PMID: 25541375 DOI: 10.1016/j.biocel.2014.11.019
    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive target for cancer therapy due to its ability to selectively induce apoptosis in cancer cells, without causing significant toxicity in normal tissues. We previously reported that galactoxyloglucan (PST001) possesses significant antitumor and immunomodulatory properties. However, the exact mechanism in mediating this anticancer effect is unknown. This study, for the first time, indicated that PST001 sensitizes non-small cell lung cancer (A549) and nasopharyngeal (KB) cells to TRAIL-mediated apoptosis. In vitro studies suggested that PST001 induced apoptosis primarily via death receptors and predominantly activated caspases belonging to the extrinsic apoptotic cascade. Microarray profiling of PST001 treated A549 and KB cells showed the suppression of survivin (BIRC5) and anti-apoptotic Bcl-2, as well as increased cytochrome C. TaqMan low density array analysis of A549 cells also confirmed that the induction of apoptosis by the polysaccharide occurred through the TRAIL-DR4/DR5 pathways. This was finally confirmed by in silico analysis, which revealed that PST001 binds to TRAIL-DR4/DR5 complexes more strongly than TNF and Fas ligand-receptor complexes. In summary, our results suggest the potential of PST001 to be developed as an anticancer agent that not only preserves innate biological activity of TRAIL, but also sensitizes cancer cells to TRAIL-mediated apoptosis.
    Matched MeSH terms: Chromatin/drug effects; Chromatin/metabolism
  3. Sex chromatin positive nuclei in the nasal smears of the females
    Sen Gupta BN
    Med J Malaya, 1968 Sep;23(1):32-4.
    PMID: 4237553
    Matched MeSH terms: Sex Chromatin*
  4. Klinefelter's syndrome, a case report
    Kutty MK, Dutt AK, Lopez G, Ramanathan K, Pillay DR, Omar-Ahmad UD
    Med J Malaya, 1968 Sep;23(1):51-3.
    PMID: 4237557
    Matched MeSH terms: Sex Chromatin*
  5. Fulltext Regions of very low H3K27me3 partition the Drosophila genome into topological domains
    El-Sharnouby S, Fischer B, Magbanua JP, Umans B, Flower R, Choo SW, et al.
    PLoS One, 2017;12(3):e0172725.
    PMID: 28282436 DOI: 10.1371/journal.pone.0172725
    It is now well established that eukaryote genomes have a common architectural organization into topologically associated domains (TADs) and evidence is accumulating that this organization plays an important role in gene regulation. However, the mechanisms that partition the genome into TADs and the nature of domain boundaries are still poorly understood. We have investigated boundary regions in the Drosophila genome and find that they can be identified as domains of very low H3K27me3. The genome-wide H3K27me3 profile partitions into two states; very low H3K27me3 identifies Depleted (D) domains that contain housekeeping genes and their regulators such as the histone acetyltransferase-containing NSL complex, whereas domains containing moderate-to-high levels of H3K27me3 (Enriched or E domains) are associated with regulated genes, irrespective of whether they are active or inactive. The D domains correlate with the boundaries of TADs and are enriched in a subset of architectural proteins, particularly Chromator, BEAF-32, and Z4/Putzig. However, rather than being clustered at the borders of these domains, these proteins bind throughout the H3K27me3-depleted regions and are much more strongly associated with the transcription start sites of housekeeping genes than with the H3K27me3 domain boundaries. While we have not demonstrated causality, we suggest that the D domain chromatin state, characterised by very low or absent H3K27me3 and established by housekeeping gene regulators, acts to separate topological domains thereby setting up the domain architecture of the genome.
    Matched MeSH terms: Chromatin/metabolism; Chromatin/chemistry; Chromatin Immunoprecipitation
  6. Fulltext A Fuzzy-C-Means-Clustering Approach: Quantifying Chromatin Pattern of Non-Neoplastic Cervical Squamous Cells
    Tang JR, Mat Isa NA, Ch'ng ES
    PLoS One, 2015;10(11):e0142830.
    PMID: 26560331 DOI: 10.1371/journal.pone.0142830
    Despite the effectiveness of Pap-smear test in reducing the mortality rate due to cervical cancer, the criteria of the reporting standard of the Pap-smear test are mostly qualitative in nature. This study addresses the issue on how to define the criteria in a more quantitative and definite term. A negative Pap-smear test result, i.e. negative for intraepithelial lesion or malignancy (NILM), is qualitatively defined to have evenly distributed, finely granular chromatin in the nuclei of cervical squamous cells. To quantify this chromatin pattern, this study employed Fuzzy C-Means clustering as the segmentation technique, enabling different degrees of chromatin segmentation to be performed on sample images of non-neoplastic squamous cells. From the simulation results, a model representing the chromatin distribution of non-neoplastic cervical squamous cell is constructed with the following quantitative characteristics: at the best representative sensitivity level 4 based on statistical analysis and human experts' feedbacks, a nucleus of non-neoplastic squamous cell has an average of 67 chromatins with a total area of 10.827 μm2; the average distance between the nearest chromatin pair is 0.508 μm and the average eccentricity of the chromatin is 0.47.
    Matched MeSH terms: Chromatin/chemistry*
  7. Chemical composition and cytotoxic properties of Clinacanthus nutans root extracts
    Teoh PL, Cheng AY, Liau M, Lem FF, Kaling GP, Chua FN, et al.
    Pharm Biol, 2017 Dec;55(1):394-401.
    PMID: 27931178
    CONTEXT: Clinacanthus nutans Lindau (Acanthaceae) is a medicinal plant that has been reported to have anti-inflammatory, antiviral, antimicrobial and antivenom activities. In Malaysia, it has been widely claimed to be effective in various cancer treatments but scientific evidence is lacking.

    OBJECTIVE: This study investigates the chemical constituents, anti-proliferative, and apoptotic properties of C. nutans root extracts.

    MATERIALS AND METHODS: The roots were subjected to solvent extraction using methanol and ethyl acetate. The anti-proliferative effects of root extracts were tested at the concentrations of 10 to 50 μg/mL on MCF-7 and HeLa by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay for 72 h. Morphological changes were observed under light microscope. Pro-apoptotic effects of root extracts were examined using flow cytometric analysis and RT-PCR. The chemical compositions of root extracts were detected using GC-MS.

    RESULTS: The proliferation of MCF-7 cells was inhibited with the IC50 values of 35 and 30 μg/mL, respectively, for methanol and ethyl acetate root extracts. The average inhibition of HeLa cells was ∼25%. Induction of apoptosis in MCF-7 was supported by chromatin condensation, down-regulation of BCL2 and unaltered expression of BAX. However, only ethyl acetate extract caused the loss of mitochondrial membrane potential. GC-MS analysis revealed the roots extracts were rich with terpenoids and phytosterols.

    DISCUSSION AND CONCLUSIONS: The results demonstrated that root extracts promote apoptosis by suppressing BCL2 via mitochondria-dependent or independent manner. The identified compounds might work solely or cooperatively in regulating apoptosis. However, further studies are required to address this.

    Matched MeSH terms: Chromatin Assembly and Disassembly/drug effects
  8. Fulltext Cancer reversion with oocyte extracts is mediated by cell cycle arrest and induction of tumour dormancy
    Saad N, Alberio R, Johnson AD, Emes RD, Giles TC, Clarke P, et al.
    Oncotarget, 2018 Mar 23;9(22):16008-16027.
    PMID: 29662623 DOI: 10.18632/oncotarget.24664
    Inducing stable control of tumour growth by tumour reversion is an alternative approach to cancer treatment when eradication of the disease cannot be achieved. The process requires re-establishment of normal control mechanisms that are lost in cancer cells so that abnormal proliferation can be halted. Embryonic environments can reset cellular programmes and we previously showed that axolotl oocyte extracts can reprogram breast cancer cells and reverse their tumorigenicity. In this study, we analysed the gene expression profiles of oocyte extract-treated tumour xenografts to show that tumour reprogramming involves cell cycle arrest and acquisition of a quiescent state. Tumour dormancy is associated with increased P27 expression, restoration of RB function and downregulation of mitogen-activated signalling pathways. We also show that the quiescent state is associated with increased levels of H4K20me3 and decreased H4K20me1, an epigenetic profile leading to chromatin compaction. The epigenetic reprogramming induced by oocyte extracts is required for RB hypophosphorylation and induction of P27 expression, both occurring during exposure to the extracts and stably maintained in reprogrammed tumour xenografts. Therefore, this study demonstrates the value of oocyte molecules for inducing tumour reversion and for the development of new chemoquiescence-based therapies.
    Matched MeSH terms: Chromatin
  9. Fulltext Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation
    Ghoussaini M, Edwards SL, Michailidou K, Nord S, Cowper-Sal Lari R, Desai K, et al.
    Nat Commun, 2014 Sep 23;4:4999.
    PMID: 25248036 DOI: 10.1038/ncomms5999
    GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
    Matched MeSH terms: Chromatin/metabolism
  10. Fulltext alpha-Mangostin enhances betulinic acid cytotoxicity and inhibits cisplatin cytotoxicity on HCT 116 colorectal carcinoma cells
    Aisha AF, Abu-Salah KM, Ismail Z, Majid AM
    Molecules, 2012;17(3):2939-54.
    PMID: 22402764 DOI: 10.3390/molecules17032939
    Despite the progress in colon cancer treatment, relapse is still a major obstacle. Hence, new drugs or drug combinations are required in the battle against colon cancer. α-Mangostin and betulinic acid (BA) are cytotoxic compounds that work by inducing the mitochondrial apoptosis pathway, and cisplatin is one of the most potent broad spectrum anti-tumor agents. This study aims to investigate the enhancement of BA cytotoxicity by α-mangostin, and the cytoprotection effect of α-mangostin and BA on cisplatin-induced cytotoxicity on HCT 116 human colorectal carcinoma cells. Cytotoxicity was investigated by the XTT cell proliferation test, and the apoptotic effects were investigated on early and late markers including caspases-3/7, mitochondrial membrane potential, cytoplasmic shrinkage, and chromatin condensation. The effect of α-mangostin on four signalling pathways was also investigated by the luciferase assay. α-Mangostin and BA were more cytotoxic to the colon cancer cells than to the normal colonic cells, and both compounds showed a cytoprotective effect against cisplatin-induced cytotoxicity. On the other hand, α-mangostin enhanced the cytotoxic and apoptotic effects of BA. Combination therapy hits multiple targets, which may improve the overall response to the treatment, and may reduce the likelihood of developing drug resistance by the tumor cells. Therefore, α-mangostin and BA may provide a novel combination for the treatment of colorectal carcinoma. The cytoprotective effect of the compounds against cisplatin-induced cytotoxicity may find applications as chemopreventive agents against carcinogens, irradiation and oxidative stress, or to neutralize cisplatin side effects.
    Matched MeSH terms: Chromatin/drug effects
  11. δ- and γ-tocotrienols induce classical ultrastructural apoptotic changes in human T lymphoblastic leukemic cells
    Wong RS, Radhakrishnan AK, Ibrahim TA, Cheong SK
    Microsc Microanal, 2012 Jun;18(3):462-9.
    PMID: 22640960 DOI: 10.1017/S1431927612000177
    Tocotrienols are isomers of the vitamin E family, which have been reported to exert cytotoxic effects in various cancer cells. Although there have been some reports on the effects of tocotrienols in leukemic cells, ultrastructural evidence of tocotrienol-induced apoptotic cell death in leukemic cells is lacking. The present study investigated the effects of three isomers of tocotrienols (alpha, delta, and gamma) on a human T lymphoblastic leukemic cell line (CEM-SS). Cell viability assays showed that all three isomers had cytotoxic effects (p < 0.05) on CEM-SS cells with delta-tocotrienol being the most potent. Transmission electron microscopy showed that the cytotoxic effects by delta- and gamma-tocotrienols were through the induction of an apoptotic pathway as demonstrated by the classical ultrastructural apoptotic changes characterized by peripheral nuclear chromatin condensation and nuclear fragmentation. These findings were confirmed biochemically by the demonstration of phosphatidylserine externalization via flow cytometry analysis. This is the first study showing classical ultrastructural apoptotic changes induced by delta- and gamma-tocotrienols in human T lymphoblastic leukemic cells.
    Matched MeSH terms: Chromatin/ultrastructure
  12. Fulltext Subtractive hybridization identifies stem cell-associated genes in an acute myeloid leukemia with poor prognosis
    Ngiow Shin Foong, Maha Abdullah, Jasmine Lim, Cheong Soon-Keng, Seow Heng-Fong
    Malaysian Journal of Medicine and Health Sciences, 2016;12(1):19-31.
    MyJurnal
    Introduction: Current prognostic markers have improved survival prediction, however, it has not
    advanced treatment strategies. Gene expression profiling may identify biological markers suitable as
    therapeutic targets. Leukaemia stem cell is associated with adverse outcome, however, its biological
    characteristics are still being investigated. We observed higher in vitro cell viability in acute myeloid
    leukaemia (AML) samples with poor prognosis, which may be stem cell related. Objective: The
    objective of this study was to profile highly expressed genes in an AML sample of poor prognosis/high
    viability and compare with a sample of good prognosis/low viability. Method: Subtractive hybridization
    was performed on two AML samples with high blast counts (>80%), a poor prognosis, PP (disease free
    survival, DFS12 months) sample. The PP sample had
    higher CD34+ counts (73% vs 46%) and higher cell viability than the GP sample. cDNA libraries were
    subsequently cloned and sequenced. Results: cDNA subtracted from the PP samples was identified
    as genes active during fetal/embryonic development (LCOR, CNOT1, ORMDL1), HOX- related genes
    (HOXA3, PBX3, SF3B1), hematopoiesis (SELL, IL-3RA) and aerobic glycolysis/hypoxia (PGK1,
    HIGD1A) -associated genes. Majority of GP clones isolated contained genes involved in oxidative
    phosphorylation, OXPHOS (COXs, ATPs, MTND4 and MTRNR2), protein synthesis (including
    ribosomal proteins, initiating and elongation factors), chromatin remodeling (H2AFZ, PTMA), cell
    motility (MALAT1, CALM2, TMSB4X), and mitochondria (HSPA9, MPO) genes. Conclusion: Thus,
    the PP sample exhibited stem cell-like features while the GP sample showed cells at a high level of cell
    activity. These genes are potential prognostic markers and targets for therapy.
    Matched MeSH terms: Chromatin Assembly and Disassembly
  13. Fulltext Differential expression patterns of leukaemia associated genes in leukaemia cell lines compared to healthy controls
    Ang Pei-Shen, Rajesh Ramasamy, Noor Hamidah Hussin, Cheong Soon-Keng, Seow Heng-Fong, Maha Abdullah
    Malaysian Journal of Medicine and Health Sciences, 2016;12(1):0-0.
    MyJurnal
    Introduction: The phenotype and genotype of cancer cells portray hallmarks of cancer which may
    have clinical value. Cancer cell lines are ideal models to study and confirm these characteristics. We
    previously established two subtracted cDNA libraries with differentially expressed genes from an
    acute myeloid leukaemia patient with poor prognosis (PP) and good prognosis (GP). Objective: To
    compare gene expression of the leukaemia associated genes with selected biological characteristics
    in leukaemia cell lines and normal controls. Methodology: Expression of 28 PP genes associated
    with early fetal/embryonic development, HOX-related genes, hematopoiesis and aerobic glycolysis/
    hypoxia genes and 36 GP genes involved in oxidative phosphorylation, protein synthesis, chromatin
    remodelling and cell motility were examined in B-lymphoid (BV173, Reh and RS4;11) and myeloid
    (HL-60, K562) leukaemia cell lines after 72h in culture as well as peripheral blood mononuclear cells
    from healthy controls (N=5) using semi-quantitative polymerase chain reaction (PCR) method. Cell
    cycle profiles were analysed on flow cytometry while MTT cytotoxicity assay was used to determine
    drug resistance to epirubicin. Results: Genes expressed significantly higher in B-lymphoid leukaemia
    cell lines compared to healthy controls were mostly of the GP library i.e. oxidative phosphorylation
    (3/10), protein synthesis (4/11), chromatin remodelling (3/3) and actin cytoskeleton genes (1/5). Only
    two genes with significant difference were from the PP library. Cancer associated genes, HSPA9 and
    PSPH (GP library) and BCAP31 (PP library) were significantly higher in the B-lymphoid leukemia cell
    lines. No significant difference was observed between myeloid cell lines and healthy controls. This
    may also be due heterogeneity of cell lines studied. PBMC from healthy controls were not in cell cycle.
    G2/M profiles and growth curves showed B-lymphoid cells just reaching plateau after 72 hour culture
    while myeloid cells were declining. IC50 values from cytotoxicity assay revealed myeloid cell lines had
    an average 13-fold higher drug resistance to epirubicin compared to B-lymphoid cell lines. Only CCL1,
    was expressed at least two-fold higher in myeloid compared to B-lymphoid cell lines. In contrast,
    MTRNR2, EEF1A1, PTMA, HLA-DR, C6orf115, PBX3, ENPP4, SELL, and IL3Ra were expressed
    more than 2-fold higher in B-lymphoid compared to myeloid cell lines studied here. Conclusion: Thus,
    B-lymphoid leukaemia cell lines here exhibited active, proliferating characteristics closer to GP genes.
    Higher expression of several genes in B-lymphoid compared to myeloid leukaemia cell lines may be
    useful markers to study biological differences including drug resistance between lineages.
    Matched MeSH terms: Chromatin; Chromatin Assembly and Disassembly
  14. Rare k-mer DNA: Identification of sequence motifs and prediction of CpG island and promoter
    Mohamed Hashim EK, Abdullah R
    J Theor Biol, 2015 Dec 21;387:88-100.
    PMID: 26427337 DOI: 10.1016/j.jtbi.2015.09.014
    Empirical analysis on k-mer DNA has been proven as an effective tool in finding unique patterns in DNA sequences which can lead to the discovery of potential sequence motifs. In an extensive study of empirical k-mer DNA on hundreds of organisms, the researchers found unique multi-modal k-mer spectra occur in the genomes of organisms from the tetrapod clade only which includes all mammals. The multi-modality is caused by the formation of the two lowest modes where k-mers under them are referred as the rare k-mers. The suppression of the two lowest modes (or the rare k-mers) can be attributed to the CG dinucleotide inclusions in them. Apart from that, the rare k-mers are selectively distributed in certain genomic features of CpG Island (CGI), promoter, 5' UTR, and exon. We correlated the rare k-mers with hundreds of annotated features using several bioinformatic tools, performed further intrinsic rare k-mer analyses within the correlated features, and modeled the elucidated rare k-mer clustering feature into a classifier to predict the correlated CGI and promoter features. Our correlation results show that rare k-mers are highly associated with several annotated features of CGI, promoter, 5' UTR, and open chromatin regions. Our intrinsic results show that rare k-mers have several unique topological, compositional, and clustering properties in CGI and promoter features. Finally, the performances of our RWC (rare-word clustering) method in predicting the CGI and promoter features are ranked among the top three, in eight of the CGI and promoter evaluations, among eight of the benchmarked datasets.
    Matched MeSH terms: Chromatin
  15. Fulltext In vitro ultramorphological assessment of apoptosis induced by zerumbone on (HeLa)
    Abdel Wahab SI, Abdul AB, Alzubairi AS, Mohamed Elhassan M, Mohan S
    J Biomed Biotechnol, 2009;2009:769568.
    PMID: 19343171 DOI: 10.1155/2009/769568
    Zerumbone (ZER), a potential anticancer compound, isolated from the fresh rhizomes of Zingiber zerumbet. In this investigation, the cytotoxic properties of ZER were evaluated, on cancer cells of human cervix (HeLa), breast and ovary, and normal cells of Chinese Hamster ovary, using MTT assay. Apoptogenic effects of ZER on HeLa were studied using fluorescence microscopy (AO/PI double staining), scanning and transmission electron microscopy (SEM and TEM), and colorimetric assay of the apoptosis promoter enzyme, caspase-3. The results of MTT assay showed that ZER has less effect on normal cells compared to cancer cells. The lowest IC(50) of ZER was observed on HeLa cells. Cytological observations showed nuclear and chromatin condensation, cell shrinkage, multinucleation, abnormalities of mitochondrial cristae, membrane blebbing, holes, cytoplasmic extrusions and formation of apoptotic bodies as confirmed collectively by double staining of AO/PI, SEM and TEM. Statistical analysis (two-tailed t-test) of differential counting of 200 cells under fluorescence microscope revealed significant difference in apoptotic cells populations between treated and untreated HeLa cells. In addition, ZER has increased the cellular level of caspase-3 on the treated HeLa cells. It could be concluded that ZER was able to produce distinctive morphological features of cell death that corresponds to apoptosis.
    Matched MeSH terms: Chromatin/drug effects
  16. Fulltext RNA-seq and ChIP-seq as Complementary Approaches for Comprehension of Plant Transcriptional Regulatory Mechanism
    Muhammad II, Kong SL, Akmar Abdullah SN, Munusamy U
    Int J Mol Sci, 2019 Dec 25;21(1).
    PMID: 31881735 DOI: 10.3390/ijms21010167
    The availability of data produced from various sequencing platforms offer the possibility to answer complex questions in plant research. However, drawbacks can arise when there are gaps in the information generated, and complementary platforms are essential to obtain more comprehensive data sets relating to specific biological process, such as responses to environmental perturbations in plant systems. The investigation of transcriptional regulation raises different challenges, particularly in associating differentially expressed transcription factors with their downstream responsive genes. In this paper, we discuss the integration of transcriptional factor studies through RNA sequencing (RNA-seq) and Chromatin Immunoprecipitation sequencing (ChIP-seq). We show how the data from ChIP-seq can strengthen information generated from RNA-seq in elucidating gene regulatory mechanisms. In particular, we discuss how integration of ChIP-seq and RNA-seq data can help to unravel transcriptional regulatory networks. This review discusses recent advances in methods for studying transcriptional regulation using these two methods. It also provides guidelines for making choices in selecting specific protocols in RNA-seq pipelines for genome-wide analysis to achieve more detailed characterization of specific transcription regulatory pathways via ChIP-seq.
    Matched MeSH terms: Chromatin Immunoprecipitation
  17. Fulltext Combined protein- and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM
    Maiti AK, Kim-Howard X, Motghare P, Pradhan V, Chua KH, Sun C, et al.
    Hum Mol Genet, 2014 Aug 1;23(15):4161-76.
    PMID: 24608226 DOI: 10.1093/hmg/ddu106
    Integrin alpha M (ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system. We previously identified a missense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecular mechanisms of this variant are incompletely understood. A meta-analysis of published and novel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10(-90), odds ratio (OR) = 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels in monocytes from patients with each rs1143679 genotype. We observed that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' < 'AG' < 'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10- to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. We found that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid- and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE.
    Matched MeSH terms: Chromatin/metabolism; Chromatin/pathology
  18. Fulltext Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy
    Mohseni J, Zabidi-Hussin ZA, Sasongko TH
    Genet Mol Biol, 2013 Sep;36(3):299-307.
    PMID: 24130434 DOI: 10.1590/S1415-47572013000300001
    Histone acetylation plays an important role in regulation of transcription in eukaryotic cells by promoting a more relaxed chromatin structure necessary for transcriptional activation. Histone deacetylases (HDACs) remove acetyl groups and suppress gene expression. HDAC inhibitors (HDACIs) are a group of small molecules that promote gene transcription by chromatin remodeling and have been extensively studied as potential drugs for treating of spinal muscular atrophy. Various drugs in this class have been studied with regard to their efficacy in increasing the expression of survival of motor neuron (SMN) protein. In this review, we discuss the current literature on this topic and summarize the findings of the main studies in this field.
    Matched MeSH terms: Chromatin; Chromatin Assembly and Disassembly
  19. Fulltext Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells
    Pfister NT, Fomin V, Regunath K, Zhou JY, Zhou W, Silwal-Pandit L, et al.
    Genes Dev., 2015 Jun 15;29(12):1298-315.
    PMID: 26080815 DOI: 10.1101/gad.263202.115
    Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.
    Matched MeSH terms: Chromatin Assembly and Disassembly/genetics*
  20. Epigenetic changes and their relationship to somaclonal variation: a need to monitor the micropropagation of plantation crops
    Azizi P, Hanafi MM, Sahebi M, Harikrishna JA, Taheri S, Yassoralipour A, et al.
    Funct Plant Biol, 2020 05;47(6):508-523.
    PMID: 32349860 DOI: 10.1071/FP19077
    Chromatin modulation plays important roles in gene expression regulation and genome activities. In plants, epigenetic changes, including variations in histone modification and DNA methylation, are linked to alterations in gene expression. Despite the significance and potential of in vitro cell and tissue culture systems in fundamental research and marketable applications, these systems threaten the genetic and epigenetic networks of intact plant organs and tissues. Cell and tissue culture applications can lead to DNA variations, methylation alterations, transposon activation, and finally, somaclonal variations. In this review, we discuss the status of the current understanding of epigenomic changes that occur under in vitro conditions in plantation crops, including coconut, oil palm, rubber, cotton, coffee and tea. It is hoped that comprehensive knowledge of the molecular basis of these epigenomic variations will help researchers develop strategies to enhance the totipotent and embryogenic capabilities of tissue culture systems for plantation crops.
    Matched MeSH terms: Chromatin
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