Abstract
A subset of our body’s tissues is continuously renewed through cell division. Tissue-specific stem cells support this tissue turnover, and understanding the mechanisms that control the behavior of these stem cells is important to understanding the health of the tissue. In this work, we identify a novel regulator of the intestinal stem cells. We find that, when the transcription factor YY1 is inactivated, intestinal stem cells can no longer renew themselves. We show that YY1 controls mitochondrial gene expression, and loss of YY1 results in loss of mitochondrial structural integrity. This work, therefore, provides a link between a mitochondrial regulator and stem cell function and broadens our appreciation of metabolic regulation in tissue-specific stem cells.
The intestinal stem cell fuels the highest rate of tissue turnover in the body and has been implicated in intestinal disease and cancer; understanding the regulatory mechanisms controlling intestinal stem cell physiology is of great importance. Here, we provide evidence that the transcription factor YY1 is essential for intestinal stem cell renewal. We observe that YY1 loss skews normal homeostatic cell turnover, with an increase in proliferating crypt cells and a decrease in their differentiated villous progeny. Increased crypt cell numbers come at the expense of Lgr5
+
stem cells. On YY1 deletion, Lgr5
+
cells accelerate their commitment to the differentiated population, exhibit increased levels of apoptosis, and fail to maintain stem cell renewal. Loss of
Yy1
in the intestine is ultimately fatal. Mechanistically, YY1 seems to play a role in stem cell energy metabolism, with mitochondrial complex I genes bound directly by YY1 and their transcript levels decreasing on YY1 loss. These unappreciated YY1 functions broaden our understanding of metabolic regulation in intestinal stem cell homeostasis.