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Fulltext Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

den Hoed J, de Boer E, Voisin N, Dingemans AJM, Guex N, Wiel L, et al.

Am J Hum Genet, 2021 02 04;108(2):346-356.
PMID: 33513338 DOI: 10.1016/j.ajhg.2021.01.007

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Matched MeSH terms: Chromatin/metabolism
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
Fulltext Large-scale 3D chromatin reconstruction from chromosomal contacts

Zhang Y, Liu W, Lin Y, Ng YK, Li S

BMC Genomics, 2019 Apr 04;20(Suppl 2):186.
PMID: 30967119 DOI: 10.1186/s12864-019-5470-2

BACKGROUND: Recent advances in genome analysis have established that chromatin has preferred 3D conformations, which bring distant loci into contact. Identifying these contacts is important for us to understand possible interactions between these loci. This has motivated the creation of the Hi-C technology, which detects long-range chromosomal interactions. Distance geometry-based algorithms, such as ChromSDE and ShRec3D, have been able to utilize Hi-C data to infer 3D chromosomal structures. However, these algorithms, being matrix-based, are space- and time-consuming on very large datasets. A human genome of 100 kilobase resolution would involve ∼30,000 loci, requiring gigabytes just in storing the matrices.
RESULTS: We propose a succinct representation of the distance matrices which tremendously reduces the space requirement. We give a complete solution, called SuperRec, for the inference of chromosomal structures from Hi-C data, through iterative solving the large-scale weighted multidimensional scaling problem.
CONCLUSIONS: SuperRec runs faster than earlier systems without compromising on result accuracy. The SuperRec package can be obtained from http://www.cs.cityu.edu.hk/~shuaicli/SuperRec .

Matched MeSH terms: Chromatin/genetics; Chromatin/chemistry*
3D TECA hydrogel reduces cellular senescence and enhances fibroblasts migration in wound healing

Younis LT, Abu Hassan MI, Taiyeb Ali TB, Bustami TJ

Asian J Pharm Sci, 2018 Jul;13(4):317-325.
PMID: 32104405 DOI: 10.1016/j.ajps.2017.12.003

This study was designed to investigate the effect of 3D TECA hydrogel on the inflammatory-induced senescence marker, and to assess the influence of the gel on the periodontal ligament fibroblasts (PDLFs) migration in wound healing in vitro. PDLFs were cultured with 20 ng/ml TNF-α to induce inflammation in the presence and absence of 50 µM 3D TECA gel for 14 d. The gel effect on the senescence maker secretory associated-β-galactosidase (SA-β-gal) activity was measured by a histochemical staining. Chromatin condensation and DNA synthesis of the cells were assessed by 4',6-diamidino-2-phenylindole and 5-ethynyl-2'-deoxyuridine fluorescent staining respectively. For evaluating fibroblasts migration, scratch wound healing assay and Pro-Plus Imaging software were used. The activity of senescence marker, SA-β-gal, was positive in the samples with TNF-α-induced inflammation. SA-β-gal percentage is suppressed (>65%, P Chromatin foci were obvious in the non-treated samples. DNA synthesis was markedly recognized by the fluorescent staining in the treated compared to non-treated cultures. Scratch wound test indicated that the cells migration rate was significantly higher (14.9 µm2/h, P

Matched MeSH terms: Chromatin; Heterochromatin
Fulltext Leea indica Ethyl Acetate Fraction Induces Growth-Inhibitory Effect in Various Cancer Cell Lines and Apoptosis in Ca Ski Human Cervical Epidermoid Carcinoma Cells

Yau Hsiung W, Abdul Kadir H

Evid Based Complement Alternat Med, 2011;2011:293060.
PMID: 21423690 DOI: 10.1155/2011/293060

The anticancer potential of Leea indica, a Chinese medicinal plant was investigated for the first time. The crude ethanol extract and fractions (ethyl acetate, hexane, and water) of Leea indica were evaluated their cytotoxicity on various cell lines (Ca Ski, MCF 7, MDA-MB-435, KB, HEP G2, WRL 68, and Vero) by MTT assay. Leea indica ethyl acetate fraction (LIEAF) was found showing the greatest cytotoxic effect against Ca Ski cervical cancer cells. Typical apoptotic morphological changes such as DNA fragmentation and chromatin condensation were observed in LIEAF-treated cells. Early signs of apoptosis such as externalization of phosphatidylserine and disruption of mitochondrial membrane potential indicated apoptosis induction. This was further substantiated by dose- and time-dependent accumulation of sub-G(1) cells, depletion of intracellular glutathione, and activation of caspase-3. In conclusion, these results suggested that LIEAF inhibited cervical cancer cells growth by inducing apoptosis and could be developed as potential anticancer drugs.

Matched MeSH terms: Chromatin
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
Salzmann's nodular degeneration of the cornea

Vannas A, Hogan MJ, Wood I

Am J Ophthalmol, 1975 Feb;79(2):211-9.
PMID: 46719

Eleven corneal specimens from nine patients with Salzmann's nodular degeneration of the cornea, together with all available clinical information, were collected for this study. The specimens were examined by light and electron microscopy. An antecedent keratitis was diagnosed by history and microscopic findings in every case. The corneal epithelium showed degenerative changes, its thickness varied, and in nodular areas it often consisted of only a single layer of flattened epithelial cells by light microscopy. Bowman's membrane was missing over the nodules, and in this zone there was excessive secretion of a basement membrane-like material. Hyaline degeneration of collagen, cellular debris, and electron-dense hyaline deposits were seen in the collagen of the nodules. The number of fibrocytes in the nodules varied from many that were active to a few that were degenerating. External irritation because of poor epithelial protection was interpreted as a causative factor, although other tissue repair mechanisms may also have played a role.

Matched MeSH terms: Chromatin
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
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*
Fulltext The Cytotoxic Properties of Baeckea frutescens Branches Extracts in Eliminating Breast Cancer Cells

Shahruzaman SH, Mustafa MF, Ramli S, Maniam S, Fakurazi S, Maniam S

Evid Based Complement Alternat Med, 2019;2019:9607590.
PMID: 31178918 DOI: 10.1155/2019/9607590

Breast cancer is the leading cause of cancer death in women in over 100 countries worldwide and accounts for almost 1 in 4 cancer cases among women. Baeckea frutescens of the family Myrtaceae has been used in traditional medicine and is known to possess antibacterial, antipyretic, and cytoprotective properties. In this study, we investigated the role of Baeckea frutescens branches extracts against human breast cancer cells. Baeckea frutescens branches extracts were prepared using Soxhlet apparatus with solvents of different polarity. The selective cytotoxic activity and the glucose consumption rate of Baeckea frutescens branches extracts of various concentrations (20 to 160 ug/ml) at 24-, 48-, and 72-hour time points were studied using MTT and glucose uptake assay. The IC50 values in human breast cancer (MCF-7 and MDA-MB-231) and mammary breast (MCF10A) cell lines were determined. Apoptotic study using AO/PI double staining was performed using fluorescent microscopy. The glucose uptake was measured using 2-NBDG, a fluorescent glucose analogue. The phytochemical screening of major secondary metabolites in plants was performed. This study reports that Baeckea frutescens branches extracts showed potent selective cytotoxic activity against MCF-7 cells compared to MDA-MB-231 cells after 72 hours of treatment. Evidence of early apoptosis which includes membrane blebbing and chromatin condensation was observed after 72 hours of treatment with Baeckea frutescens branches extracts. Interestingly, for the glucose uptake assay, the inhibition was observed as early as 24 hours upon treatment. All Baeckea frutescens extracts showed the presence of major secondary metabolites such as tannin, triterpenoid, flavonoid, and phenol. However, alkaloid level was unable to be determined. The identification of Baeckea frutescens and its possible role in selectively inhibiting glucose consumption in breast cancer cells defines a new role of natural product that can be utilised as an effective agent that regulates metabolic reprogramming in breast cancer.

Matched MeSH terms: Chromatin
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*
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
Fulltext The use of protein-DNA, chromatin immunoprecipitation, and transcriptome arrays to describe transcriptional circuits in the dehydrated male rat hypothalamus

Qiu J, Kleineidam A, Gouraud S, Yao ST, Greenwood M, Hoe SZ, et al.

Endocrinology, 2014 Nov;155(11):4380-90.
PMID: 25144923 DOI: 10.1210/en.2014-1448

The supraoptic nucleus (SON) of the hypothalamus is responsible for maintaining osmotic stability in mammals through its elaboration of the antidiuretic hormone arginine vasopressin. Upon dehydration, the SON undergoes a function-related plasticity, which includes remodeling of morphology, electrical properties, and biosynthetic activity. This process occurs alongside alterations in steady state transcript levels, which might be mediated by changes in the activity of transcription factors. In order to identify which transcription factors might be involved in changing patterns of gene expression, an Affymetrix protein-DNA array analysis was carried out. Nuclear extracts of SON from dehydrated and control male rats were analyzed for binding to the 345 consensus DNA transcription factor binding sequences of the array. Statistical analysis revealed significant changes in binding to 26 consensus elements, of which EMSA confirmed increased binding to signal transducer and activator of transcription (Stat) 1/Stat3, cellular Myelocytomatosis virus-like cellular proto-oncogene (c-Myc)-Myc-associated factor X (Max), and pre-B cell leukemia transcription factor 1 sequences after dehydration. Focusing on c-Myc and Max, we used quantitative PCR to confirm previous transcriptomic analysis that had suggested an increase in c-Myc, but not Max, mRNA levels in the SON after dehydration, and we demonstrated c-Myc- and Max-like immunoreactivities in SON arginine vasopressin-expressing cells. Finally, by comparing new data obtained from Roche-NimbleGen chromatin immunoprecipitation arrays with previously published transcriptomic data, we have identified putative c-Myc target genes whose expression changes in the SON after dehydration. These include known c-Myc targets, such as the Slc7a5 gene, which encodes the L-type amino acid transporter 1, ribosomal protein L24, histone deactylase 2, and the Rat sarcoma proto-oncogene (Ras)-related nuclear GTPase.

Matched MeSH terms: Chromatin Immunoprecipitation*
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*
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
Fulltext Induction of selective cytotoxicity and apoptosis in human T4-lymphoblastoid cell line (CEMss) by boesenbergin a isolated from boesenbergia rotunda rhizomes involves mitochondrial pathway, activation of caspase 3 and G2/M phase cell cycle arrest

Ng KB, Bustamam A, Sukari MA, Abdelwahab SI, Mohan S, Buckle MJ, et al.

BMC Complement Altern Med, 2013;13:41.
PMID: 23432947 DOI: 10.1186/1472-6882-13-41

Boesenbergia rotunda (Roxb.) Schlecht (family zingiberaceae) is a rhizomatous herb that is distributed from north-eastern India to south-east Asia, especially in Indonesia, Thailand and Malaysia. Previous research has shown that the crude extract of this plant has cytotoxic properties. The current study examines the cytotoxic properties of boesenbergin A isolated from Boesenbergia rotunda.

Matched MeSH terms: Chromatin/metabolism
Modelling of chromatin morphologies in breast cancer cells undergoing apoptosis using generalized Cauchy field

Muniandy SV, Stanslas J

Comput Med Imaging Graph, 2008 Oct;32(7):631-7.
PMID: 18707844 DOI: 10.1016/j.compmedimag.2008.07.003

Chromatin morphologies in human breast cancer cells treated with an anti-cancer agent are analyzed at their early stage of programmed cell death or apoptosis. The gray-level images of nuclear chromatin are modelled as random fields. We used two-dimensional isotropic generalized Cauchy field to characterize local self-similarity and global long-range dependence behaviors in the image spatial data. Generalized Cauchy field allows the description of fractal behavior inferred from fractal dimension and the long-range dependence inferred from correlation exponent to be carried out independently. We demonstrated the usefulness of locally self-similar random fields with long-range dependence for modelling chromatin condensation.

Matched MeSH terms: Chromatin/pathology*; Chromatin/ultrastructure*
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
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
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

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