Telomere epigenetics in stem cells and cancers

Introduction Linear eukaryotic chromosomes pose special challenges to the cellular machinery, namely the end-protection problem and the end-replication problem. Firstly, the chromosome ends have to be protected from being recognised as double strand breaks (DSBs), which would erroneously activate DNA damage response (DDR) pathways, resulting in DNA degradation and/or chromosome fusion events. This is referred to as the ‘end-protection’ problem. Secondly, as a result of the ‘end-replication’ problem, chromosomes risk gradual loss of genomic information with each cell division, as there is incomplete replication of the 5’ end of the linear DNA template by canonical DNA polymerases. Specialised ribonucleoprotein complexes found at chromosome ends, called telomeres, provide solutions to both of these problems. In human cells, telomeres consist of tandem arrays of ‘TTAGGG’ DNA repeats, bound by a telomere(definition)-specific complex, called shelterin (1). The shelterin complex loops the telomere DNA repeats into a higher-order structure that shields the chromosome ends from DDR that would otherwise inappropriately repair the telomere as a doublestranded break. Proper telomere function requires a continual maintenance of a minimum length of TTAGGG repeats as critically short telomeres signal proliferation arrest and cell death. During replication, telomere DNA is replenished by a reverse-transcriptase called telomerase, which uses an RNA template (TERC) to synthesise telomere repeat DNA to counteract the erosion of DNA ends (2). Telomerase activity is tightly regulated during development and has a very low, almost undetectable activity in somatic cells. In humans, telomerase expression is limited to highly proliferative tissues that harbor progenitor or stem cell compartments. There is a well-established correlation between the life span of cells and telomere shortening. Shorter telomere lengths have been linked to human health conditions, many of which are age-related. They have been reported in patients suffering from age-related diabetes, cardiovascular disease, migraines and increased risk of neurodegenerative diseases (3-6). Direct evidence for the importance of telomere length in human disease derives from patients with mutations in TERT and TERC, the genes encoding the reverse transcriptase and RNA component of telomerase, respectively (7,8). These diseases are characterised by rapid telomere attrition, and thus, patients have shorter telomeres and exhibit compromised regenerative capacity of tissues, particularly in highly proliferative tissues such as bone marrow, epithelial cells and liver. One example of such human diseases is dyskeratosis congenita (DC), a premature aging syndrome linked to mutations in the telomerase complex, resulting in decreased telomerase stability and shorter telomeres. Patients with DC develop numerous different pathologies, including short stature, bone marrow failure, skin defects, hematopoietic defects, infertility and premature death. These patients are also susceptible to developing cancer. Another example of a human disease that involves a telomerase mutation is aplastic anemia. Individuals with aplastic anemia also show accelerated telomere shortening and die young. Consistently, mouse models of telomerase deficiency also show affected maintenance and regeneration of tissues that undergo extensive proliferation, further implicating the impact of short telomere length on health conditions (9). In this article, we provide an overview of telomere structure and chromatin, and how cells maintain the crucial balance between telomere attrition and extension that determines telomere homeostasis in somatic cells. We will discuss emerging evidence showing that embryonic stem (ES) cells have very different telomere chromatin dynamics, indicating that telomere chromatin metabolism changes as cells differentiate and age. We will also describe how disruption to telomere homeostasis could lead to diseased states such as cancer (Fig. 1).