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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
The effect of non-coding DNA variations on P53 and cMYC competitive inhibition at cis-overlapping motifs
Katherine Kin1, Xi Chen1, Manuel Gonzalez-Garay2
1Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX 77054, USA and.
Abstract:
Non-coding DNA variations play a critical role in increasing the risk for development of common complex diseases, and account for the majority of SNPs highly associated with cancer. However, it remains a challenge to identify etiologic variants and to predict their pathological effects on target gene expression for clinical purposes. Cis-overlapping motifs (COMs) are elements of enhancer regions that impact gene expression by enabling competitive binding and switching between transcription factors. Mutations within COMs are especially important when the involved transcription factors have opposing effects on gene regulation, like P53 tumor suppressor and cMYC proto-oncogene. In this study, genome-wide analysis of ChIP-seq data from human cancer and mouse embryonic cells identified a significant number of putative regulatory elements with signals for both P53 and cMYC. Each co-occupied element contains, on average, two COMs, and one common SNP every two COMs. Gene ontology of predicted target genes for COMs showed that the majority are involved in DNA damage, apoptosis, cell cycle regulation, and RNA processing. EMSA results showed that both cMYC and P53 bind to cis-overlapping motifs within a ChIP-seq co-occupied region in Chr12. In vitro functional analysis of selected co-occupied elements verified enhancer activity, and also showed that the occurrence of SNPs within three COMs significantly altered enhancer activity. We identified a list of COM-associated functional SNPs that are in close proximity to SNPs associated with common diseases in large population studies. These results suggest a potential molecular mechanism to identify etiologic regulatory mutations associated with common diseases.
Insights
Non-coding DNA variations linked to complex diseases can be identified using cis-overlapping motifs (COMs). These motifs, involving transcription factors like P53 and cMYC, reveal how mutations impact gene expression and disease risk.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Non-coding DNA variations, particularly single nucleotide polymorphisms (SNPs), are major contributors to complex diseases and cancer risk.
- Identifying pathogenic variants and predicting their impact on gene expression remains a significant challenge for clinical applications.
- Cis-overlapping motifs (COMs) within enhancers regulate gene expression through competitive transcription factor binding, especially when factors have opposing roles, such as P53 and cMYC.
Purpose of the Study:
- To identify regulatory variants in non-coding DNA associated with complex diseases.
- To investigate the role of cis-overlapping motifs (COMs) and their interaction with transcription factors P53 and cMYC in gene regulation.
- To explore the functional impact of SNPs within COMs on enhancer activity and their proximity to disease-associated SNPs.
Main Methods:
- Genome-wide analysis of ChIP-seq data from human cancer and mouse embryonic cells to identify co-occupied regulatory elements by P53 and cMYC.
- Bioinformatic analysis to identify COMs and common SNPs within these elements.
- Gene ontology analysis to predict the function of target genes regulated by COMs.
- Electrophoretic Mobility Shift Assay (EMSA) to confirm P53 and cMYC binding to COMs.
- In vitro functional assays to assess enhancer activity and the impact of SNPs within COMs.
Main Results:
- A significant number of putative regulatory elements co-occupied by P53 and cMYC were identified.
- Each co-occupied element contained an average of two COMs, with one common SNP per two COMs.
- Functional analysis confirmed enhancer activity and demonstrated that SNPs within COMs significantly altered this activity.
- A list of COM-associated functional SNPs was identified in proximity to known disease-associated SNPs.
Conclusions:
- Cis-overlapping motifs (COMs) represent key regulatory elements where transcription factor binding influences gene expression.
- SNPs within COMs can alter enhancer activity, providing a molecular mechanism for the etiologic role of non-coding variants in common diseases.
- This study provides a framework for identifying functional regulatory mutations contributing to complex disease risk.
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