Ectopic expression of meiotic cohesin generates chromosome instability in cancer cell line
Abdelhalim Boukaba1, Jian Liu1, Carl Ward2
1Molecular Epigenetics Laboratory, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
Abstract:
Many tumors express meiotic genes that could potentially drive somatic chromosome instability. While germline cohesin subunits SMC1B, STAG3, and REC8 are widely expressed in many cancers, messenger RNA and protein for RAD21L subunit are expressed at very low levels. To elucidate the potential of meiotic cohesins to contribute to genome instability, their expression was investigated in human cell lines, predominately in DLD-1. While the induction of the REC8 complex resulted in a mild mitotic phenotype, the expression of the RAD21L complex produced an arrested but viable cell pool, thus providing a source of DNA damage, mitotic chromosome missegregation, sporadic polyteny, and altered gene expression. We also found that genomic binding profiles of ectopically expressed meiotic cohesin complexes were reminiscent of their corresponding specific binding patterns in testis. Furthermore, meiotic cohesins were found to localize to the same sites as BORIS/CTCFL, rather than CTCF sites normally associated with the somatic cohesin complex. These findings highlight the existence of a germline epigenomic memory that is conserved in cells that normally do not express meiotic genes. Our results reveal a mechanism of action by unduly expressed meiotic cohesins that potentially links them to aneuploidy and chromosomal mutations in affected cells.
Insights
Tumors expressing meiotic cohesin genes, like RAD21L, can cause genome instability. Ectopic expression of these genes in cancer cells leads to DNA damage, chromosome missegregation, and altered gene expression, linking them to aneuploidy.
Area of Science:
- Genetics
- Cancer Biology
- Epigenetics
Background:
- Many tumors aberrantly express meiotic genes, potentially contributing to somatic chromosome instability.
- While some germline cohesin subunits are common in cancers, RAD21L expression is notably low.
Purpose of the Study:
- To investigate the role of meiotic cohesin subunits in driving genome instability in cancer cells.
- To elucidate the functional consequences of ectopic meiotic cohesin expression in human cell lines.
Main Methods:
- Expression analysis of meiotic cohesin subunits (SMC1B, STAG3, REC8, RAD21L) in human cell lines (DLD-1).
- Induction of REC8 and RAD21L complexes to assess their impact on cell phenotype and genome integrity.
- Chromatin immunoprecipitation sequencing to determine genomic binding profiles of meiotic cohesins.
Main Results:
- Induction of REC8 caused mild mitotic defects, while RAD21L expression led to a viable but arrested cell pool with DNA damage and chromosome missegregation.
- Ectopically expressed meiotic cohesins exhibited testis-specific binding patterns and localized with BORIS/CTCFL, distinct from somatic cohesin's CTCF association.
- Aberrant meiotic cohesin expression induced polyteny and altered gene expression profiles.
Conclusions:
- Ectopic expression of meiotic cohesins in non-germline cells can disrupt genome stability, leading to aneuploidy and chromosomal mutations.
- These findings suggest a conserved 'germline epigenomic memory' mechanism linking meiotic genes to cancer genome instability.
- Meiotic cohesins may represent novel therapeutic targets for cancers exhibiting aberrant expression patterns.
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