scholarly journals TopBP1 contains transcriptional regulatory domains and regulates gene pathways involved in breast cancer

2008 ◽  
Vol 10 (S2) ◽  
Author(s):  
RHG Wright ◽  
ES Dornan ◽  
MM Donaldson ◽  
M MacFarlane ◽  
P Herzyk ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regulatory Domains ◽  
Transcriptional Regulatory

scholarly journals Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens

2021 ◽  
Vol 7 (27) ◽  
pp. eabf5733
Author(s):  
Rui Lopes ◽  
Kathleen Sprouffske ◽  
Caibin Sheng ◽  
Esther C. H. Uijttewaal ◽  
Adriana Emma Wesdorp ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regulatory Networks ◽  
Essential Role ◽  
Regulatory Elements ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory ◽  
Functional Relevance ◽  
Genome Scale ◽  
Transcription Program

Millions of putative transcriptional regulatory elements (TREs) have been cataloged in the human genome, yet their functional relevance in specific pathophysiological settings remains to be determined. This is critical to understand how oncogenic transcription factors (TFs) engage specific TREs to impose transcriptional programs underlying malignant phenotypes. Here, we combine cutting edge CRISPR screens and epigenomic profiling to functionally survey ≈15,000 TREs engaged by estrogen receptor (ER). We show that ER exerts its oncogenic role in breast cancer by engaging TREs enriched in GATA3, TFAP2C, and H3K27Ac signal. These TREs control critical downstream TFs, among which TFAP2C plays an essential role in ER-driven cell proliferation. Together, our work reveals novel insights into a critical oncogenic transcription program and provides a framework to map regulatory networks, enabling to dissect the function of the noncoding genome of cancer cells.

scholarly journals DNA-dependent homodimerization, sub-cellular partitioning, and protein destabilization control WUSCHEL levels and spatial patterning

2016 ◽  
Vol 113 (41) ◽  
pp. E6307-E6315 ◽  
Author(s):  
Kevin Rodriguez ◽  
Mariano Perales ◽  
Stephen Snipes ◽  
Ram Kishor Yadav ◽  
Mercedes Diaz-Mendoza ◽  
...  
Keyword(s):  
Dna Binding ◽  
Nuclear Export ◽  
Spatial Patterning ◽  
Nuclear Retention ◽  
Regulatory Domains ◽  
Stem Cell Maintenance ◽  
Protein Levels ◽  
Transcriptional Regulatory ◽  
Responsive Element ◽  
Nuclear Levels

The homeodomain transcription factor WUSCHEL (WUS) promotes stem cell maintenance in inflorescence meristems of Arabidopsis thaliana. WUS, which is synthesized in the rib meristem, migrates and accumulates at lower levels in adjacent cells. Maintenance of WUS protein levels and spatial patterning distribution is not well-understood. Here, we show that the last 63-aa stretch of WUS is necessary for maintaining different levels of WUS protein in the rib meristem and adjacent cells. The 63-aa region contains the following transcriptional regulatory domains: the acidic region, the WUS-box, which is conserved in WUS-related HOMEOBOX family members, and the ethylene-responsive element binding factor-associated amphiphilic repression (EAR-like) domain. Our analysis reveals that the opposing functions of WUS-box, which is required for nuclear retention, and EAR-like domain, which participates in nuclear export, are necessary to maintain higher nuclear levels of WUS in cells of the rib meristem and lower nuclear levels in adjacent cells. We also show that the N-terminal DNA binding domain, which is required for both DNA binding and homodimerization, along with the homodimerization sequence located in the central part of the protein, restricts WUS from spreading excessively and show that the homodimerization is critical for WUS function. Our analysis also reveals that a higher level of WUS outside the rib meristem leads to protein destabilization, suggesting a new tier of regulation in WUS protein regulation. Taken together our data show that processes that influence WUS protein levels and spatial distribution are highly coupled to its transcriptional activity.

scholarly journals Pan-Cancer Drivers Are Recurrent Transcriptional Regulatory Heterogeneities in Early-Stage Luminal Breast Cancer

2021 ◽  
Vol 81 (7) ◽  
pp. 1840-1852 ◽  
Author(s):  
Shambhavi Singh ◽  
Matthew D. Sutcliffe ◽  
Kathy Repich ◽  
Kristen A. Atkins ◽  
Jennifer A. Harvey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Luminal Breast Cancer ◽  
Transcriptional Regulatory ◽  
Cancer Drivers ◽  
Pan Cancer

scholarly journals Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery

2018 ◽  
Author(s):  
Xinchen Wang ◽  
David B. Goldstein
Keyword(s):  
Complex Disease ◽  
Genome Wide Association Study ◽  
Regulatory Elements ◽  
Disease Genes ◽  
Transcriptional Regulatory Elements ◽  
Regulatory Domains ◽  
Disease Gene Discovery ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Transcriptional Regulatory

AbstractNon-coding transcriptional regulatory elements are critical for controlling the spatiotemporal expression of genes. Here, we demonstrate that the number of bases in enhancers linked to a gene reflects its disease pathogenicity. Moreover, genes with redundant enhancer domains are depleted of cis-acting genetic variants that disrupt gene expression, and are buffered against the effects of disruptive non-coding mutations. Our results demonstrate that dosage-sensitive genes have evolved robustness to the disruptive effects of genetic variation by expanding their regulatory domains. This resolves a puzzle in the genetic literature about why disease genes are depleted of cis-eQTLs, suggesting that eQTL information may implicate the wrong genes at genome-wide association study loci, and establishes a framework for identifying non-coding regulatory variation with phenotypic consequences.

Breast Cancer Transcriptional Regulatory Network Reprogramming by using the CRISPR/Cas9 system: An Oncogenetics Perspective

2021 ◽  
Vol 21 ◽  
Author(s):  
Desh Deepak Singh ◽  
Ravi Verma ◽  
Subhash K. Tripathi ◽  
Rajnish Sahu ◽  
Poonam Trivedi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Transcriptional Regulatory Network ◽  
Treatment Options ◽  
Diagnostic Tools ◽  
Transcriptional Regulatory Networks ◽  
Development Of Resistance ◽  
Transcriptional Regulatory ◽  
Network Reprogramming

: Breast cancer (BC) is the second most commonly diagnosed cancer in the world. BC develops due to dysregulation of transcriptional profiles, substantial interpatient variations, genetic mutations, and dysregulation of signaling pathways in breast cells. These events are regulated by many genes such as BRCA1/2, PTEN, TP53, mTOR, TERT, AKT, PI3K and others genes. Treatment options for BC remain a hurdle, which warrants a comprehensive understanding that establishes an interlinking connection between these genes in BC tumorigenesis. Consequently, there is an increasing demand for alternative treatment approaches and the design of more effective treatments. In this regard, it is crucial to build the corresponding transcriptional regulatory networks governing BC by using advanced genetic tools and techniques. In the past, several molecular editing technologies have been used to edit genes with several limitations. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR Associated Protein 9 (CRISPR/Cas9) recently received a profound attention due to its potential in biomedical and therapeutic applications. Here, we review the role of various molecular signalling pathways dysregulated in BC development such as PTEN/PI3K/AKT/mTOR as well as BRCA1/BRCA2/TP53/TERT and their interplay between the related gene networks in BC initiation, progression and development of resistance against available targeted therapeutic agents. Use of CRISPR/Cas9 gene-editing technology to generate BC gene-specific transgenic cell lines and animal models to decipher their role and interactions with other gene products has been employed successfully. Moreover, the significance of using CRISPR/Cas9 technology to develop early BC diagnostic tools and treatments is discussed here.

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