Elucidating Telomerase Function Using Genetically Defined Human Stem Cell Models
2013 new Scholar Award in aging
Human cells undergo a process called cellular aging that limits the number of times they can divide, thereby setting the self-renewal capacity of human tissues. One measurement of a cell’s age is how often it has divided and how many cells it can still give rise to in the future. This information is molecularly encoded at the end of each chromosome in a DNA structure called the telomere. Telomeres are repetitive DNA sequences that protect the end of the chromosome from being recognized as sites of DNA damage. With each cell division the telomeres of most cells shorten and this progressive DNA loss triggers a growth arrest that prohibits the cell from dividing further. As a result, telomere length is a marker of a cell’s age. Aberrant telomere shortening can lead to premature cellular aging while bypassing this telomere-induced growth arrest mechanism can cause cells to divide too often, promoting the formation of tumors. Although this important biological relationship between telomeres, cancer and aging has long been appreciated, many fundamental questions that directly relate to human disease and human aging remain unanswered. Specifically, the underlying molecular processes that regulate telomere shortening in human tissues are not well understood. Telomere shortening occurs in human cells because the enzyme telomerase that adds DNA to the telomere is only active in few cell types, namely stem cells, and is turned off in most other human cells. One reason why we know little about this process of telomerase silencing is because specific telomerase regulation naturally occurs only in human cells but not in mouse cells, a widely used model organism where telomerase is active in all cell types. As a consequence, telomerase regulation and telomere shortening cannot be studied in mice and must be understood in the context of a primary human cell system. We have recently developed the use of site-specific nucleases to genetically engineer human pluripotent stem cells, which can be maintained indefinitely and differentiated into any cell type of interest. As a result we now have an appropriate human cell system with which to address the mechanisms of telomere regulation during cellular aging and the early steps of tumor formation. Specifically, we are investigating how telomerase is selectively silenced during the process of converting a stem cell to a differentiated cell, how telomerase is recruited to telomeres in human cells, and the mechanisms by which telomerase becomes reactivated in human tumors. Through these studies we hope to understand the basic principles of human telomere biology, and how alterations in the structure and function of telomeres could lead to age-related disease.