scholarly journals Building a schizophrenia genetic network: Transcription Factor 4 regulates genes involved in neuronal development and schizophrenia risk

2017 ◽  
Author(s):  
Hanzhang Xia ◽  
Fay M. Jahr ◽  
Nak-Kyeong Kim ◽  
Linying Xie ◽  
Andrey A. Shabalin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Neuronal Development ◽  
Pyramidal Neurons ◽  
Genetic Network ◽  
Binding Motif ◽  
Gene Set ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Sirna Knockdown ◽  
Transcription Factor 4

ABSTRACTThe transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SZ association findings. We identified 11,322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having ≥1 Ebox) and implicate a gene set enriched for genes down-regulated in TCF4 siRNA knockdown experiments, indicating the validity of our findings. The TCF4 gene set was also enriched among 1) Gene Ontology categories such as axon/neuronal development, 2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex, and 3) genes down-regulated in post-mortem brain tissue from SZ patients (OR=2.8, permutation p<4x10−5). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA binding proteins such as FOXP2 and the SZ-associated EP300. TCF4 binding sites were modestly enriched among SZ risk loci from the Psychiatric Genomic Consortium (OR=1.56, p=0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site ±10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. These findings confirm TCF4 as an important regulator of neural genes and point towards functional interactions with potential relevance for SZ.

scholarly journals Building a schizophrenia genetic network: transcription factor 4 regulates genes involved in neuronal development and schizophrenia risk

2018 ◽  
Vol 27 (18) ◽  
pp. 3246-3256 ◽  
Author(s):  
Hanzhang Xia ◽  
Fay M Jahr ◽  
Nak-Kyeong Kim ◽  
Linying Xie ◽  
Andrey A Shabalin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Neuronal Development ◽  
Genetic Network ◽  
Transcription Factor 4

scholarly journals Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast

1993 ◽  
Vol 90 (23) ◽  
pp. 11371-11375 ◽  
Author(s):  
J Y Chan ◽  
X L Han ◽  
Y W Kan
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Leucine Zipper ◽  
Genetic Selection ◽  
Yeast Cells ◽  
Binding Motif ◽  
Related Factor ◽  
Transcriptional Activators ◽  
Basic Leucine Zipper ◽  
Related Transcription Factor

We have devised a complementation assay in yeast to clone mammalian transcriptional activators and have used it to identify a human basic leucine-zipper transcription factor that we have designated Nrf1 for NF-E2-related factor 1. Nrf1 potentially encodes a 742-aa protein and displays marked homology to the mouse and human NF-E2 transcription factors. Nrf1 activates transcription via NF-E2 binding sites in yeast cells. The ubiquitous expression pattern of Nrf1 and the range of promoters containing the NF-E2 binding motif suggest that this gene may play a role in the regulation of heme synthesis and ferritin genes.

scholarly journals Systematic Evaluation of DNA Sequence Variations on in vivo Transcription Factor Binding Affinity

2021 ◽  
Vol 12 ◽  
Author(s):  
Yutong Jin ◽  
Jiahui Jiang ◽  
Ruixuan Wang ◽  
Zhaohui S. Qin
Keyword(s):  
Transcription Factor ◽  
Binding Affinity ◽  
Binding Sites ◽  
Association Studies ◽  
Systematic Evaluation ◽  
Binding Motif ◽  
Genome Wide Association Studies ◽  
Single Nucleotide Variants ◽  
Protein Coding

The majority of the single nucleotide variants (SNVs) identified by genome-wide association studies (GWAS) fall outside of the protein-coding regions. Elucidating the functional implications of these variants has been a major challenge. A possible mechanism for functional non-coding variants is that they disrupted the canonical transcription factor (TF) binding sites that affect the in vivo binding of the TF. However, their impact varies since many positions within a TF binding motif are not well conserved. Therefore, simply annotating all variants located in putative TF binding sites may overestimate the functional impact of these SNVs. We conducted a comprehensive survey to study the effect of SNVs on the TF binding affinity. A sequence-based machine learning method was used to estimate the change in binding affinity for each SNV located inside a putative motif site. From the results obtained on 18 TF binding motifs, we found that there is a substantial variation in terms of a SNV’s impact on TF binding affinity. We found that only about 20% of SNVs located inside putative TF binding sites would likely to have significant impact on the TF-DNA binding.

scholarly journals Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor E2F.

1996 ◽  
Vol 16 (4) ◽  
pp. 1659-1667 ◽  
Author(s):  
J Karlseder ◽  
H Rotheneder ◽  
E Wintersberger
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Binding Sites ◽  
Promoter Activity ◽  
Binding Motif ◽  
Transcription Machinery ◽  
Transcription Factor E2f

Within the region around 150 bp upstream of the initiation codon, which was previously shown to suffice for growth-regulated expression, the murine thymidine kinase gene carries a single binding site for transcription factor Sp1; about 10 bp downstream of this site, there is a binding motif for transcription factor E2F. The latter protein appears to be responsible for growth regulation of the promoter. Mutational inactivation of either the Sp1 or the E2F site almost completely abolishes promoter activity, suggesting that the two transcription factors interact directly in delivering an activation signal to the basic transcription machinery. This was verified by demonstrating with the use of glutathione S-transferase fusion proteins that E2F and Sp1 bind to each other in vitro. For this interaction, the C-terminal part of Sp1 and the N terminus of E2F1, a domain also present in E2F2 and E2F3 but absent in E2F4 and E2F5, were essential. Accordingly, E2F1 to E2F3 but not E2F4 and E2F5 were found to bind sp1 in vitro. Coimmunoprecipitation experiments showed that complexes exist in vivo, and it was estabilished that the distance between the binding sites for the two transcription factors was critical for optimal promoter activity. Finally, in vivo footprinting experiments indicated that both the sp1 and E2F binding sites are occupied throughout the cell cycle. Mutation of either binding motif abolished binding of both transcription factors in vivo, which may indicate cooperative binding of the two proteins to chromatin-organized DNA. Our data are in line with the hypothesis that E2F functions as a growth- and cell cycle regulated tethering factor between Sp1 and the basic transcription machinery.

scholarly journals SEMplMe: A tool for integrating DNA methylation effects in transcription factor binding affinity predictions

2020 ◽  
Author(s):  
Sierra S. Nishizaki ◽  
Alan P. Boyle
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Binding Sites ◽  
Human Disease ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Binding Motif ◽  
Factor Binding ◽  
Genome Bisulfite Sequencing ◽  
Aberrant Dna Methylation

AbstractMotivationAberrant DNA methylation in transcription factor binding sites has been shown to lead to anomalous gene regulation that is strongly associated with human disease. However, the majority of methylation-sensitive positions within transcription factor binding sites remain unknown. Here we introduce SEMplMe, a computational tool to generate predictions of the effect of methylation on transcription factor binding strength in every position within a transcription factor’s motif.ResultsSEMplMe uses ChIP-seq and whole genome bisulfite sequencing to predict effects of methylation within binding sites. SEMplMe validates known methylation sensitive and insensitive positions within a binding motif, identifies cell type specific transcription factor binding driven by methylation, and outperforms SELEX-based predictions. These predictions can be used to identify aberrant sites of DNA methylation contributing to human disease.Availability and ImplementationSEMplMe is available from https://github.com/Boyle-Lab/[email protected]

scholarly journals Motif elucidation in ChIP-seq datasets with a knockout control

2019 ◽  
Author(s):  
Danielle Denisko ◽  
Coby Viner ◽  
Michael M. Hoffman
Keyword(s):  
Transcription Factor ◽  
Chromatin Immunoprecipitation ◽  
Binding Sites ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Negative Control ◽  
Differential Analysis ◽  
Wild Type ◽  
Factor Binding ◽  
Chromatin Immunoprecipitation Sequencing

AbstractChromatin immunoprecipitation-sequencing (ChIP-seq) is widely used to find transcription factor binding sites, but suffers from various sources of noise. Knocking out the target factor mitigates noise by acting as a negative control. Paired wild-type and knockout experiments can generate improved motifs but require optimal differential analysis. We introduce peaKO—a method to automatically optimize motif analyses with knockout controls, which we compare to two other methods. PeaKO often improves elucidation of the target factor and highlights the benefits of knockout controls, which far outperform input controls. It is freely available at https://peako.hoffmanlab.org.

scholarly journals 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

2020 ◽  
Vol 21 (17) ◽  
pp. 6141
Author(s):  
Keunsoo Kang ◽  
Yoonjung Choi ◽  
Hoo Hyun Kim ◽  
Kyung Hyun Yoo ◽  
Sungryul Yu
Keyword(s):  
Cell Cycle ◽  
Gene Regulation ◽  
Cell Lines ◽  
Binding Sites ◽  
Binding Motif ◽  
Cell Type ◽  
Gene Set ◽  
Genome Wide ◽  
Cell Type Specific ◽  
Mcf 7

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.

Sign in / Sign up

Export Citation Format

Share Document