Yy1-Mediated Polycomb Group Function Safeguards Hematopoietic Stem Cells From Premature Aging
Our bodies rely on special cells called hematopoietic stem cells (HSCs) to continuously produce all types of blood cells throughout our lives. As we age, these vital stem cells can start to decline, leading to problems like a skewed balance in blood cell production, where more myeloid cells (like those involved in immunity and clotting) are made at the expense of lymphoid cells (which are key for adaptive immunity). This decline also involves HSCs losing their “quiescence,” meaning they divide more frequently instead of resting, and their metabolism becomes imbalanced.
Scientists have been trying to understand the molecular reasons behind this age-related decline. A recent study sheds light on a crucial player: a protein called YY1. YY1 is a “transcription factor,” meaning it helps control which genes are turned on or off. It also belongs to a group of proteins called Polycomb group (PcG) proteins, which are known for their role in “silencing” genes, essentially keeping them inactive.
This research focused on a specific part of the YY1 protein, called the REPO domain, which is essential for its Polycomb function. When this REPO domain was removed in a model system, the HSCs showed signs of premature aging. They expanded in number but lost their ability to self-renew long-term, meaning they couldn’t sustain blood cell production effectively. These cells also exhibited the myeloid-biased differentiation seen in aging, along with reduced quiescence, increased levels of harmful molecules called reactive oxygen species, and altered metabolic activity—all classic indicators of cellular aging.
These findings reveal that the Polycomb function of YY1 acts as a critical “epigenetic mechanism.” Epigenetics refers to changes in gene activity that don’t involve altering the underlying DNA sequence itself, but rather how genes are expressed. In this case, YY1’s Polycomb activity helps maintain the youthful state of HSCs by preserving their metabolic balance, ensuring they can self-renew for a long time, and ultimately delaying their aging process.
Source: link to paper