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Updated: Jul 16, 2025
Induction and Analysis of Epithelial to Mesenchymal Transition
Published on: August 27, 2013
KDM5A noncanonically binds antagonists MLL1/2 to mediate gene regulation and promotes epithelial to mesenchymal
R Kirtana1, Soumen Manna1, Samir Kumar Patra1
1Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008, India.
Abstract:
Differential expression of genes involved in certain processes is a collaborative outcome of crosstalk between signalling molecules and epigenetic modifiers. In response to environmental stimulus, interplay between transcription factors and epigenetic modifiers together dictates the regulation of genes. MLLs and KDM5A are functionally antagonistic proteins, as one acts as a writer and the other erases the active chromatin mark, i.e., H3K4me3. KDM5A influences the process of EMT by binding to both epithelial and mesenchymal gene promoters. Through this work, we show that when bound to E-cadherin promoter, KDM5A acts as a classical repressor by demethylating H3K4me3, but on mesenchymal markers, it acts as a transcriptional activator by inhibiting the activity of HDACs and increasing H3K18ac. Further, through our chromatin immunoprecipitation experiments, we observed a co-occupancy of KDM5A with MLLs, we tested whether KDM5A might physically interact with MLLs and WDR5, and here we provide experimental evidence that KDM5A indeed interacts with MLLs and WDR5.
Insights
KDM5A acts as both a repressor and activator in gene regulation by modifying chromatin marks like H3K4me3 and H3K18ac. This study reveals KDM5A interacts with MLLs and WDR5, impacting gene expression.
Area of Science:
- Epigenetics and Gene Regulation
- Molecular Biology
- Cellular Signaling
Background:
- Gene expression is regulated by the interplay of signaling molecules, epigenetic modifiers, and transcription factors.
- MLLs (writers) and KDM5A (erasers) antagonistically regulate the active chromatin mark H3K4me3.
- KDM5A plays a role in Epithelial-Mesenchymal Transition (EMT) by interacting with gene promoters.
Purpose of the Study:
- To elucidate the dual role of KDM5A as a repressor and activator in gene regulation.
- To investigate the interaction of KDM5A with MLLs and WDR5.
- To understand KDM5A's mechanism in regulating epithelial and mesenchymal gene expression.
Main Methods:
- Chromatin immunoprecipitation (ChIP) assays.
- Analysis of KDM5A binding to E-cadherin and mesenchymal marker promoters.
- Assessment of KDM5A's effect on histone modifications (H3K4me3, H3K18ac) and HDAC activity.
- Co-immunoprecipitation to test physical interactions between KDM5A, MLLs, and WDR5.
Main Results:
- KDM5A represses E-cadherin promoter activity by demethylating H3K4me3.
- KDM5A activates mesenchymal markers by inhibiting HDACs and increasing H3K18ac.
- Chromatin immunoprecipitation confirmed co-occupancy of KDM5A with MLLs.
- Experimental evidence demonstrated physical interaction between KDM5A, MLLs, and WDR5.
Conclusions:
- KDM5A exhibits context-dependent functions, acting as both a transcriptional repressor and activator.
- KDM5A's interaction with MLLs and WDR5 is crucial for its regulatory functions.
- These findings provide new insights into the epigenetic mechanisms governing gene expression and EMT.
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