Predicting FOXM1-Mediated Gene Regulation through the Analysis of Genome-Wide FOXM1 Binding Sites in MCF-7, K562, SK-N-SH, GM12878 and ECC-1 Cell Lines

Forkhead box protein M1 (FOXM1) is a key transcription factor (TF) that regulates a common set of genes related to the cell cycle in various cell types. However, the mechanism by which FOXM1 controls the common gene set in different cellular contexts is unclear. In this study, a comprehensive meta-analysis of genome-wide FOXM1 binding sites in ECC-1, GM12878, K562, MCF-7, and SK-N-SH cell lines was conducted to predict FOXM1-driven gene regulation. Consistent with previous studies, different TF binding motifs were identified at FOXM1 binding sites, while the NFY binding motif was found at 81% of common FOXM1 binding sites in promoters of cell cycle-related genes. The results indicated that FOXM1 might control the gene set through interaction with the NFY proteins, while cell type-specific genes were predicted to be regulated by enhancers with FOXM1 and cell type-specific TFs. We also found that the high expression level of FOXM1 was significantly associated with poor prognosis in nine types of cancer. Overall, these results suggest that FOXM1 is predicted to function as a master regulator of the cell cycle through the interaction of NFY-family proteins, and therefore the inhibition of FOXM1 could be an attractive strategy for cancer therapy.

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Epigenomic Analysis of RAD51 ChIP-seq Data Reveals cis-regulatory Elements Associated with Autophagy in Cancer Cell Lines

Cancers ◽

10.3390/cancers13112547 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2547

Author(s):

Keunsoo Kang ◽

Yoonjung Choi ◽

Hyeonjin Moon ◽

Chaelin You ◽

Minjin Seo ◽

...

Keyword(s):

Gene Regulation ◽

Homologous Recombination ◽

Cell Lines ◽

Regulatory Elements ◽

Binding Motif ◽

Genome Wide ◽

E Box ◽

Autophagy Pathway ◽

Mcf 7

RAD51 is a recombinase that plays a pivotal role in homologous recombination. Although the role of RAD51 in homologous recombination has been extensively studied, it is unclear whether RAD51 can be involved in gene regulation as a co-factor. In this study, we found evidence that RAD51 may contribute to the regulation of genes involved in the autophagy pathway with E-box proteins such as USF1, USF2, and/or MITF in GM12878, HepG2, K562, and MCF-7 cell lines. The canonical USF binding motif (CACGTG) was significantly identified at RAD51-bound cis-regulatory elements in all four cell lines. In addition, genome-wide USF1, USF2, and/or MITF-binding regions significantly coincided with the RAD51-associated cis-regulatory elements in the same cell line. Interestingly, the promoters of genes associated with the autophagy pathway, such as ATG3 and ATG5, were significantly occupied by RAD51 and regulated by RAD51 in HepG2 and MCF-7 cell lines. Taken together, these results unveiled a novel role of RAD51 and provided evidence that RAD51-associated cis-regulatory elements could possibly be involved in regulating autophagy-related genes with E-box binding proteins.

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Probing transcription factor combinatorics in different promoter classes and in enhancers

10.1101/197418 ◽

2017 ◽

Author(s):

Jimmy Vandel ◽

Océane Cassan ◽

Sophie Lèbre ◽

Charles-Henri Lecellier ◽

Laurent Bréhélin

Keyword(s):

Binding Sites ◽

Target Genes ◽

Cell Types ◽

Model Parameters ◽

Binding Motif ◽

Cell Type ◽

Regulatory Regions ◽

New Approach ◽

Cell Type Specific ◽

Common Target

In eukaryotic cells, transcription factors (TFs) are thought to act in a combinatorial way, by competing and collaborating to regulate common target genes. However, several questions remain regarding the conservation of these combina-tions among different gene classes, regulatory regions and cell types. We propose a new approach named TFcoop to infer the TF combinations involved in the binding of a tar-get TF in a particular cell type. TFcoop aims to predict the binding sites of the target TF upon the binding affinity of all identified cooperating TFs. The set of cooperating TFs and model parameters are learned from ChIP-seq data of the target TF. We used TFcoop to investigate the TF combina-tions involved in the binding of 106 TFs on 41 cell types and in four regulatory regions: promoters of mRNAs, lncRNAs and pri-miRNAs, and enhancers. We first assess that TFcoop is accurate and outperforms simple PWM methods for pre-dicting TF binding sites. Next, analysis of the learned models sheds light on important properties of TF combinations in different promoter classes and in enhancers. First, we show that combinations governing TF binding on enhancers are more cell-type specific than that governing binding in pro-moters. Second, for a given TF and cell type, we observe that TF combinations are different between promoters and en-hancers, but similar for promoters of mRNAs, lncRNAs and pri-miRNAs. Analysis of the TFs cooperating with the dif-ferent targets show over-representation of pioneer TFs and a clear preference for TFs with binding motif composition similar to that of the target. Lastly, our models accurately dis-tinguish promoters associated with specific biological processes.

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Identification of universal and cell type specific p53 DNA binding

10.1101/177667 ◽

2017 ◽

Cited By ~ 2

Author(s):

Antonina Hafner ◽

Lyubov Kublo ◽

Galit Lahav ◽

Jacob Stewart-Ornstein

Keyword(s):

Cell Lines ◽

Binding Sites ◽

Epithelial To Mesenchymal Transition ◽

Chromatin Accessibility ◽

Specific Gene ◽

Cell Type ◽

Cell Type Specificity ◽

Mesenchymal Transition ◽

Cell Type Specific ◽

Meta Analyses

AbstractThe tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell type specific gene expression programs, however recent studies and meta-analyses of genomic data propose largely uniform, and condition independent, p53 binding. To systematically assess the cell type specificity of p53, we measured its association with DNA in 12 p53 wild-type cell lines, from a range of epithelial linages, in response to ionizing radiation. We found that the majority of bound sites were occupied across all cell lines, however we also identified a subset of binding sites that were specific to one or a few cell lines. Unlike the shared p53-bound genome, which was not dependent on chromatin accessibility, the association of p53 with these atypical binding sites was well explained by chromatin accessibility and could be modulated by forcing cell state changes such as the epithelial-to-mesenchymal transition. These results position p53 as having both universal and cell type specific regulatory programs that have different regulators and dependence on chromatin state.

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Annotations capturing cell-type-specific TF binding explain a large fraction of disease heritability

10.1101/474684 ◽

2018 ◽

Cited By ~ 1

Author(s):

Bryce van de Geijn ◽

Hilary Finucane ◽

Steven Gazal ◽

Farhad Hormozdiari ◽

Tiffany Amariuta ◽

...

Keyword(s):

Gene Regulation ◽

Transcription Factors ◽

Complex Traits ◽

Complex Disease ◽

Specific Binding ◽

Large Fraction ◽

Genome Wide Association ◽

Cell Type ◽

Genome Wide ◽

Cell Type Specific

AbstractIt is widely known that regulatory variation plays a major role in complex disease and that cell-type-specific binding of transcription factors (TF) is critical to gene regulation, but genomic annotations from directly measured TF binding information are not currently available for most cell-type-TF pairs. Here, we construct cell-type-specific TF binding annotations by intersecting sequence-based TF binding predictions with cell-type-specific chromatin data; this strategy addresses both the limitation that identical sequences may be bound or unbound depending on surrounding chromatin context, and the limitation that sequence-based predictions are generally not cell-type-specific. We evaluated different combinations of sequence-based TF predictions and chromatin data by partitioning the heritability of 49 diseases and complex traits (average N=320K) using stratified LD score regression with the baseline-LD model (which is not cell-type-specific). We determined that 100bp windows around MotifMap sequenced-based TF binding predictions intersected with a union of six cell-type-specific chromatin marks (imputed using ChromImpute) performed best, with an 58% increase in heritability enrichment compared to the chromatin marks alone (11.6x vs 7.3x; P = 9 × 10-14 for difference) and a 12% increase in cell-type-specific signal conditional on annotations from the baseline-LD model (P = 8 × 10-11 for difference). Our results show that intersecting sequence-based TF predictions with cell-type-specific chromatin information can help refine genome-wide association signals.

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Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability

Human Molecular Genetics ◽

10.1093/hmg/ddz226 ◽

2019 ◽

Vol 29 (7) ◽

pp. 1057-1067 ◽

Cited By ~ 3

Author(s):

Bryce van de Geijn ◽

Hilary Finucane ◽

Steven Gazal ◽

Farhad Hormozdiari ◽

Tiffany Amariuta ◽

...

Keyword(s):

Binding Sites ◽

Complex Traits ◽

Complex Disease ◽

Specific Binding ◽

Large Fraction ◽

Cell Types ◽

Genome Wide Association ◽

Cell Type ◽

Genome Wide ◽

Cell Type Specific

Abstract Regulatory variation plays a major role in complex disease and that cell type-specific binding of transcription factors (TF) is critical to gene regulation. However, assessing the contribution of genetic variation in TF-binding sites to disease heritability is challenging, as binding is often cell type-specific and annotations from directly measured TF binding are not currently available for most cell type-TF pairs. We investigate approaches to annotate TF binding, including directly measured chromatin data and sequence-based predictions. We find that TF-binding annotations constructed by intersecting sequence-based TF-binding predictions with cell type-specific chromatin data explain a large fraction of heritability across a broad set of diseases and corresponding cell types; this strategy of constructing annotations addresses both the limitation that identical sequences may be bound or unbound depending on surrounding chromatin context and the limitation that sequence-based predictions are generally not cell type-specific. We partitioned the heritability of 49 diseases and complex traits using stratified linkage disequilibrium (LD) score regression with the baseline-LD model (which is not cell type-specific) plus the new annotations. We determined that 100 bp windows around MotifMap sequenced-based TF-binding predictions intersected with a union of six cell type-specific chromatin marks (imputed using ChromImpute) performed best, with an 58% increase in heritability enrichment compared to the chromatin marks alone (11.6× vs. 7.3×, P = 9 × 10−14 for difference) and a 20% increase in cell type-specific signal conditional on annotations from the baseline-LD model (P = 8 × 10−11 for difference). Our results show that TF-binding annotations explain substantial disease heritability and can help refine genome-wide association signals.

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RAD51 May Regulate the Expression of Genes Involved in Autophagy Through Interaction with E-box Binding Proteins in Cancer Cell Lines

10.20944/preprints202010.0452.v1 ◽

2020 ◽

Author(s):

Keunsoo Kang ◽

Yoonjung Choi ◽

Hyeonjin Moon ◽

Minjin Seo ◽

Jahyun Yoon ◽

...

Keyword(s):

Homologous Recombination ◽

Cell Lines ◽

Binding Sites ◽

Binding Proteins ◽

Binding Motif ◽

Expression Of Genes ◽

Genome Wide ◽

E Box ◽

Autophagy Pathway

RAD51 is a recombinase that plays a pivotal role in homologous recombination. Although the role of RAD51 in homologous recombination has been extensively studied, it is unclear whether RAD51 can be involved in gene regulation as a co-factor. In this study, we found in silico evidence that RAD51 may contribute to the regulation of genes involved in the autophagy pathway through interaction with E-box proteins such as USF1, USF2, and/or MITF in GM12878, HepG2, K562, and MCF-7 cell lines. The canonical USF binding motif (CACGTG) was significantly identified at RAD51 binding sites in all four cell lines. In addition, genome-wide USF1, USF2, and/or MITF-binding regions significantly coincided with the RAD51-binding sites in the same cell line. Interestingly, the promoters of genes associated with the autophagy pathway were significantly occupied by RAD51 in all four cell lines. Taken together, these results predicted a novel role of RAD51 that had not been addressed previously, and provided evidence that RAD51 could possibly be involved in regulating genes associated with the autophagy pathway, through interaction with E-box binding proteins.

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In Vitro Antitumor Evaluation of Some Hybrid Molecules Containing Coumarin and Quinolinone Moieties

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190930143856 ◽

2020 ◽

Vol 19 (16) ◽

pp. 2010-2018

Author(s):

Youstina W. Rizzk ◽

Ibrahim M. El-Deen ◽

Faten Z. Mohammed ◽

Moustafa S. Abdelhamid ◽

Amgad I.M. Khedr

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Topoisomerase Ii ◽

Cancer Cell Lines ◽

Bax Protein ◽

Hybrid Molecules ◽

Mcf 7

Background: Hybrid molecules furnished by merging two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery. Currently, coumarin hybrids have attracted the keen attention of researchers to discover their therapeutic capability against cancer. Objective: The present study aimed to evaluate the in vitro antitumor activity of a new series of hybrid molecules containing coumarin and quinolinone moieties 4 and 5 against four cancer cell lines. Materials and Methods: A new series of hybrid molecules containing coumarin and quinolinone moieties, 4a-c and 5a-c, were synthesized and screened for their cytotoxicity against prostate PC-3, breast MCF-7, colon HCT- 116 and liver HepG2 cancer cell lines as well as normal breast Hs-371 T. Results: All the synthesized compounds were assessed for their in vitro antiproliferative activity against four cancer cell lines and several compounds were found to be active. Further in vitro cell cycle study of compounds 4a and 5a revealed MCF-7 cells arrest at G2 /M phase of the cell cycle profile and induction apoptosis at pre-G1 phase. The apoptosis-inducing activity was evidenced by up-regulation of Bax protein together with the downregulation of the expression of Bcl-2 protein. The mechanism of cytotoxic activity of compounds 4a and 5a correlated to its topoisomerase II inhibitory activity. Conclusion: Hybrid molecules containing coumarin and quinolinone moieties represents a scaffold for further optimization to obtain promising anticancer agents.

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Cytometric Profiling of CD133+ Cells in Human Colon Carcinoma Cell Lines Identifies a Common core Phenotype and Cell Type-specific Mosaics

The International Journal of Biological Markers ◽

10.5301/jbm.5000020 ◽

2013 ◽

Vol 28 (3) ◽

pp. 267-273 ◽

Cited By ~ 11

Author(s):

Marica Gemei ◽

Rosa Di Noto ◽

Peppino Mirabelli ◽

Luigi Del Vecchio

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Colon Carcinoma ◽

Cell Lines ◽

Carcinoma Cell ◽

Cell Type ◽

Carcinoma Cell Lines ◽

Cell Type Specific

In colorectal cancer, CD133+ cells from fresh biopsies proved to be more tumorigenic than their CD133– counterparts. Nevertheless, the function of CD133 protein in tumorigenic cells seems only marginal. Moreover, CD133 expression alone is insufficient to isolate true cancer stem cells, since only 1 out of 262 CD133+ cells actually displays stem-cell capacity. Thus, new markers for colorectal cancer stem cells are needed. Here, we show the extensive characterization of CD133+ cells in 5 different colon carcinoma continuous cell lines (HT29, HCT116, Caco2, GEO and LS174T), each representing a different maturation level of colorectal cancer cells. Markers associated with stemness, tumorigenesis and metastatic potential were selected. We identified 6 molecules consistently present on CD133+ cells: CD9, CD29, CD49b, CD59, CD151, and CD326. By contrast, CD24, CD26, CD54, CD66c, CD81, CD90, CD99, CD112, CD164, CD166, and CD200 showed a discontinuous behavior, which led us to identify cell type-specific surface antigen mosaics. Finally, some antigens, e.g. CD227, indicated the possibility of classifying the CD133+ cells into 2 subsets likely exhibiting specific features. This study reports, for the first time, an extended characterization of the CD133+ cells in colon carcinoma cell lines and provides a “dictionary” of antigens to be used in colorectal cancer research.

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Histone modifications form a cell-type-specific chromosomal bar code that persists through the cell cycle

Scientific Reports ◽

10.1038/s41598-021-82539-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

John A. Halsall ◽

Simon Andrews ◽

Felix Krueger ◽

Charlotte E. Rutledge ◽

Gabriella Ficz ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Histone Modifications ◽

Expression Patterns ◽

Cell Types ◽

Cell Type ◽

Bar Code ◽

Genes Encoding ◽

Cell Type Specific ◽

Rolling Windows

AbstractChromatin configuration influences gene expression in eukaryotes at multiple levels, from individual nucleosomes to chromatin domains several Mb long. Post-translational modifications (PTM) of core histones seem to be involved in chromatin structural transitions, but how remains unclear. To explore this, we used ChIP-seq and two cell types, HeLa and lymphoblastoid (LCL), to define how changes in chromatin packaging through the cell cycle influence the distributions of three transcription-associated histone modifications, H3K9ac, H3K4me3 and H3K27me3. We show that chromosome regions (bands) of 10–50 Mb, detectable by immunofluorescence microscopy of metaphase (M) chromosomes, are also present in G1 and G2. They comprise 1–5 Mb sub-bands that differ between HeLa and LCL but remain consistent through the cell cycle. The same sub-bands are defined by H3K9ac and H3K4me3, while H3K27me3 spreads more widely. We found little change between cell cycle phases, whether compared by 5 Kb rolling windows or when analysis was restricted to functional elements such as transcription start sites and topologically associating domains. Only a small number of genes showed cell-cycle related changes: at genes encoding proteins involved in mitosis, H3K9 became highly acetylated in G2M, possibly because of ongoing transcription. In conclusion, modified histone isoforms H3K9ac, H3K4me3 and H3K27me3 exhibit a characteristic genomic distribution at resolutions of 1 Mb and below that differs between HeLa and lymphoblastoid cells but remains remarkably consistent through the cell cycle. We suggest that this cell-type-specific chromosomal bar-code is part of a homeostatic mechanism by which cells retain their characteristic gene expression patterns, and hence their identity, through multiple mitoses.

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