Female-Specific Epigenetic Mechanisms May Contribute to Tumor Progression | press room

Transformation of breast cancer cells into breast cancer. Credits / Inserm – Xavier Cumul

Research describes epigenetic role[1] non-coding RNA in the development of aggressive tumors, in particular breast cancer. Research carried out in collaboration with the Curie Institute, Inserm, CNRS, Paoli Calmettes Institute, Aix-Marseille University.[2]just published in a magazine Cell. These results may more broadly explain gender predisposition to certain pathologies.

All mammals have two sex chromosomes. Mammalian females have two X chromosomes, unlike males, which have an X chromosome and a Y. We already knew about the role of a specific non-coding RNA called XIST in initiating the inactivation of one of the two female X chromosomes. The purpose of this inactivation is to block the dual expression of genes located on this chromosome, as this affects the viability of the cell. In this new study, the scientists demonstrate that XIST not only plays a role in triggering this X-chromosome inactivation, but also in maintaining it throughout the life of cells.

To achieve this result, the researchers studied live consequences of removing XIST. Several techniques have been used for this. ” Either we used genetic tools to block XIST expression, or we used CRISPR techniques.[3] to interfere with expression and the XIST gene was silenced explains Rafael Margeron, Inserm researcher and head of the Polycomb Mechanism of Repression group at the Curie Institute in the Division of Genetics and Developmental Biology (Institut Curie/CNRS/Inserm/Sorbonne University).

Loss of XIST in studied cell lines[4] has a significant effect on homeostasis[5] breast tissue and influence tumor development. Rafael Margeron elaborates that ” when we study tumors and look at what the properties of these tumors were, we see that there is a tendency for the absence of XIST in the most aggressive breast tumors. As well as the reactivation of a certain number of inactive X genes.”

Genes are reactivated and transcription is gaining momentum

Among the genes reactivated upon loss of XIST, the researchers isolated the gene encoding MED14, an important subunit in the mediator protein complex. It plays a role in the control of gene expression.

Therefore, an increase in the expression of MED14 will affect the activity of the mediator and contribute to the disruption of the differentiation of breast stem cells.[6]. This is potentially the result of increased activation of enhancers. (see FOCUS below).

Finally, loss of XIST leads to the reactivation of certain genes (on the inactive X chromosome) involved in cell differentiation and affects the development of aggressive tumor cells. Since this epigenetic mechanism is specific to the presence of two X chromosomes, these results will play an important role in the study of predisposition to human sex-related pathologies.

This study suggests that XIST expression, as well as certain X-linked genes, could be used as markers of response to novel therapeutic strategies. explains Christophe Ginestier, head of the Inserm group “Epithelial stem cells and cancer” at the Center for Cancer Research in Marseille.

Focus: transcription initiation

“Expression of genes is controlled by promoters, as well as fragments of DNA that can be quite distant from the gene and promoter, called enhancers. There is a connection between enhancers and promoters. The Mediator complex is involved in this communication and allows enhancers to fine-tune gene expression. “explains Rafael Margeron.

[1] Epigenetics is the discipline that studies the mechanisms involved in the regulation of genes necessary for cells to function and maintain their identity.

[2] The work was carried out in the research unit “Genetics and Developmental Biology” (Curie Institute, CNRS, Inserm, Sorbonne University) by Rafael Margeron’s team “Mechanism of Repression by Polycomb Proteins”; at the Marseille Cancer Research Center (CRCM/Inserm, CNRS, University of Aix-Marseilles, Center for Cancer Control in the PACA Region – Paoli-Calmette Institute) by the team of Emmanuelle Charaf-Jofre and Christophe Ginestier and with EMBL in Heidelberg (Edith Hurd).

[3] The CRISPR technique (short palindromic repeats at regular intervals) involves interrupting or pausing the expression of a gene by precisely targeting it.

[4] The breast tissue contains ducts consisting of basal and luminal cells. The selected cell lines allow this tissue heterogeneity to be reproduced.

[5] Maintaining a balance between the internal and external environment.

[6] Differentiation is the ability of a cell to acquire its own function. A stem cell can become any cell (muscle, excretory, bone, etc.), but its location (and hence its environment and the transcription factors found there) will determine its future.

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