Genome-wide quantification of transcription factor binding at single-DNA-molecule resolution using methyl-transferase footprinting

Abstract Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown. Result We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. Conclusion In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.

Download Full-text

Genome-Wide Identification of Transcription Start Sites, Promoters and Transcription Factor Binding Sites in E. coli

PLoS ONE ◽

10.1371/journal.pone.0007526 ◽

2009 ◽

Vol 4 (10) ◽

pp. e7526 ◽

Cited By ~ 184

Author(s):

Alfredo Mendoza-Vargas ◽

Leticia Olvera ◽

Maricela Olvera ◽

Ricardo Grande ◽

Leticia Vega-Alvarado ◽

...

Keyword(s):

Transcription Factor ◽

Binding Sites ◽

Transcription Factor Binding Sites ◽

Transcription Factor Binding ◽

Transcription Start ◽

Transcription Start Sites ◽

E Coli ◽

Factor Binding ◽

Genome Wide

Download Full-text

Identification and characterization of constrained non-exonic bases lacking predictive epigenomic and transcription factor binding annotations

10.1101/722876 ◽

2019 ◽

Author(s):

Olivera Grujic ◽

Tanya N. Phung ◽

Soo Bin Kwon ◽

Adriana Arneson ◽

Yuju Lee ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factor Binding ◽

Regulatory Sequence ◽

Human Genetic Variation ◽

Sequence Motifs ◽

Variant Prioritization ◽

Factor Binding ◽

Genome Wide ◽

Identification And Characterization

AbstractAnnotations of evolutionarily constraint provide important information for variant prioritization. Genome-wide maps of epigenomic marks and transcription factor binding provide complementary information for interpreting a subset of such prioritized variants. Here we developed the Constrained Non-Exonic Predictor (CNEP) to quantify the evidence of each base in the human genome being in a constrained non-exonic element from over 60,000 epigenomic and transcription factor binding features. We find that the CNEP score outperforms baseline and related existing scores at predicting constrained non-exonic bases from such data. However, a subset of such bases are still not well predicted by CNEP. We developed a complementary Conservation Signature Score by CNEP (CSS-CNEP) using conservation state and constrained element annotations that is predictive of those bases. Using human genetic variation, regulatory sequence motifs, mouse epigenomic data, and retrospectively considered additional human data we further characterize the nature of constrained non-exonic bases with low CNEP scores.

Download Full-text

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

Nature Genetics ◽

10.1038/s41588-018-0196-7 ◽

2018 ◽

Vol 50 (10) ◽

pp. 1483-1493 ◽

Cited By ~ 25

Author(s):

Yakir A. Reshef ◽

Hilary K. Finucane ◽

David R. Kelley ◽

Alexander Gusev ◽

Dylan Kotliar ◽

...

Keyword(s):

Transcription Factor ◽

Disease Risk ◽

Transcription Factor Binding ◽

Factor Binding ◽

Polygenic Disease ◽

Genome Wide

Download Full-text

Genome-wide identification of transcription factors and transcription-factor binding sites in oleaginous microalgae Nannochloropsis

Scientific Reports ◽

10.1038/srep05454 ◽

2014 ◽

Vol 4 (1) ◽

Cited By ~ 47

Author(s):

Jianqiang Hu ◽

Dongmei Wang ◽

Jing Li ◽

Gongchao Jing ◽

Kang Ning ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Binding Sites ◽

Transcription Factor Binding Sites ◽

Transcription Factor Binding ◽

Factor Binding ◽

Oleaginous Microalgae ◽

Genome Wide

Download Full-text

Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

Cells ◽

10.3390/cells9061435 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1435

Author(s):

Yu-Chin Lien ◽

Paul Zhiping Wang ◽

Xueqing Maggie Lu ◽

Rebecca A. Simmons

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Transcription Factor Binding ◽

Binding Motifs ◽

Factor Binding ◽

Intrauterine Growth ◽

Gene Dysregulation ◽

Genome Wide

Intrauterine growth retardation (IUGR), which induces epigenetic modifications and permanent changes in gene expression, has been associated with the development of type 2 diabetes. Using a rat model of IUGR, we performed ChIP-Seq to identify and map genome-wide histone modifications and gene dysregulation in islets from 2- and 10-week rats. IUGR induced significant changes in the enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in both 2-wk and 10-wk islets, which were correlated with expression changes of multiple genes critical for islet function in IUGR islets. ChIP-Seq analysis showed that IUGR-induced histone mark changes were enriched at critical transcription factor binding motifs, such as C/EBPs, Ets1, Bcl6, Thrb, Ebf1, Sox9, and Mitf. These transcription factors were also identified as top upstream regulators in our previously published transcriptome study. In addition, our ChIP-seq data revealed more than 1000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. The poised state of many potential bivalent genes was altered by IUGR, particularly Acod1, Fgf21, Serpina11, Cdh16, Lrrc27, and Lrrc66, key islet genes. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes that may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.

Download Full-text