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Retroviral Scanning: Mapping MLV Integration Sites to Define Cell-specific Regulatory Regions
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Endogenous Retroviral Sequences Behave as Putative Enhancers Controlling Gene Expression through HP1-Regulated
Sébastien Calvet1, Séphora Sallis2, Nehmé Saksouk1
1Institut de Recherche en Cancérologie de Montpellier (IRCM), University of Montpellier, Inserm U1194, ICM, CNRS, F-34298 Montpellier, France.
Cells
|August 12, 2022
Summary
Loss of Heterochromatin Protein 1 (HP1) reactivates endogenous retroviruses (ERVs), forming regulatory hubs that influence gene expression and liver cancer. HP1 and H3K27me3 are crucial for silencing ERVs and associated genes.
Area of Science:
- Genomics
- Epigenetics
- Cancer Biology
Background:
- Mammalian genomes contain abundant repetitive elements, including endogenous retroviruses (ERVs), which can impact gene expression and cancer.
- Heterochromatin Protein 1 (HP1) proteins are vital for heterochromatin maintenance; their loss in liver cells promotes ERV reactivation and liver tumorigenesis.
Purpose of the Study:
- To investigate the regulatory roles of specific ERVs located upstream of genes upregulated upon HP1 loss.
- To elucidate the mechanisms by which ERVs interact with endogenous genes and how HP1 influences these interactions.
Main Methods:
- Analysis of ERV elements upstream of Mbd1 and Trim24 genes in the context of HP1 expression.
- Chromatin immunoprecipitation (ChIP) to assess enrichment of epigenetic marks (H3K9me3, H4K20me3, H3K4me1, H3K27me3) at ERVs.
- Investigation of physical looping between ERVs and endogenous gene promoters.
Main Results:
- HP1-dependent ERVs function as alternative promoters or enhancers, forming physical loops with endogenous gene promoters.
- These ERVs exhibit a unique combination of heterochromatin (H3K9me3, H4K20me3) and enhancer (H3K4me1) marks, potentially marking them as ERV-derived enhancers.
- HP1 and H3K27me3 cooperatively silence ERVs and repress associated gene expression, with enrichment of H3K27me3 being HP1-dependent.
Conclusions:
- A novel regulatory hub is identified, involving HP1-dependent physical looping between specific ERVs and endogenous genes.
- HP1 and epigenetic modifications play a critical role in controlling ERV activity and their contribution to gene regulation and tumorigenesis.
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