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Identifying two genes involved in regulating stem cells

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Adult stem cells, present in many tissues and organs, are difficult to identify and study in vivo. But studying them remains crucial for understanding the origin of cancers. In fact they have the capacity to divide and differentiate, including in cancer cells, thus helping the tumor to proliferate. The work of Louis Gervais, researcher at Institut Curie, brings new light to this area.

Understanding the mechanisms that regulate stem cells and their renewal and differentiation properties is now a major challenge in biomedical research. In recent years, stem cells have been the subject of many studies given their application in regenerative medicine, as tools for repairing or replacing defective organs. Adult stem cells are thus proposed as a primary possible source for the origin of cancers, meaning that studying them is even more vital. However, although adult, pluripotent stem cells are present in many tissues and organs (skin, intestine, muscles, brain), they remain rare and difficult to identify since they are hidden in a complex cellular environment which makes them difficult to study in vivo. The recent identification of adult intestinal stem cells in fruit flies offers new prospects for studying adult stem cells in vivo.

The epigenetic regulation of stem cells against tumor proliferation

Increasing numbers of research projects show the importance of epigenetic regulation of stem cells during development, and also in adults. A large proportion of epigenetic processes rely on dynamic modifications of chromatin (DNA or histones), which thus modulate gene expression. The research recently published in the journal Developmental Cell (Gervais et al., 2019) addresses this issue, showing in vivo how the epigenetic regulation of intestinal stem cells is vital in preventing proliferation of tumors.

Kismet and Trr: two key players in this regulation

Thanks to genetic screening, Louis Gervais, a researcher in Allison Bardin’s team (U934/UMR3215, genetics and developmental biology) and his colleagues, showed that chromatin regulators, Kismet/CHD7 and Trr/MLL3-4, are essential in maintaining the balance between proliferation and differentiation of intestinal stem cells. These genes are retained in mammals and frequently muted in cancers. They show that Kismet and Trr are strongly co-located on the entire genome, and that they jointly regulate a number of genes in intestinal stem cells. They take part in repressing the EGFR pathway by activating the expression of a pathway repressor: Cbl. These results have led us to propose that Trr and Kismet play a part in establishing the state of organization of chromatin needed to maintain a base level of proliferation of stem cells, thus limiting their anarchic expansion.

Sources

Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4