Insidious chromatin change with a propensity to exhaust intestinal stem cells during aging

During aging, tissue stem cells can demonstrate two opposing phenotypes of tissue homeostasis disruption: proliferation and exhaustion. Stem cells can exhaust as a result of excessive cell proliferation or independently of cell proliferation. There are many silent changes in chromatin structures and gene expression that are not necessarily reflected in manifested phenotypes during aging. Here through analyses of chromatin accessibility and gene expression in intestinal progenitor cells during aging, we discovered changes of chromatin accessibility and gene expression that have a propensity to exhaust intestinal stem cells (ISCs). During aging, Trithorax-like (Trl) target genes, <i>ced-6</i> and <i>ci</i>, close their chromatin structures and decrease their expression in intestinal progenitor cells. Inhibition of <i>Trl</i>, <i>ced-6</i>, or <i>ci</i> exhausts ISCs. This study provides new insight into changes of chromatin accessibility and gene expression that have a potential to exhaust ISCs during aging.