Telomere length is inherited with resetting of the telomere set-point

Abstract

We have studied models of telomerase haploinsufficiency in humans and mice to analyze regulation of telomere length and the significance of "set points" in inheritance of telomere length. In three families with clinical syndromes associated with short telomeres resulting from haploinsufficient mutations in TERT, the gene encoding telomerase reverse transcriptase, we asked whether restoration of normal genotypes in offspring of affected individuals would elongate inherited short telomeres. Telomeres were shorter than normal in some but not all genotypically normal offspring of telomerase-mutant parents or grandparents. Analysis of these findings was complicated by heterogeneity of telomere length among individuals, as well as by the admixing of telomeres inherited from affected parents with those inherited from unaffected ("wild-type" TERT) parents. To understand further the inheritance of telomere length, we established a shortened-telomere mouse model. When Tert +/− heterozygous mice were successively cross-bred through 17 generations, telomere length shortened progressively. The late-generation Tert +/− mice were intercrossed to produce genotypically wild-type Tert +/+ mice, for which telomere length was characterized. Strikingly, telomere length in these Tert +/+ mice was not longer than that of their Tert +/− parents. Moreover, when successive crosses were carried out among these short-telomere Tert +/+ offspring mice, telomere length was stable, with no elongation up to six generations. This breeding strategy therefore has established a mouse strain, B6.ST (short telomeres), with C57BL/6 genotype and stable short telomeres. These findings suggest that the set point of telomere lengths of offspring is determined by the telomere lengths of their parents in the presence of normal expression of telomerase.T elomerase is an RNA-dependent DNA polymerase that consists of two essential components, a template RNA (TERC) and a catalytic reverse transcriptase (TERT). The telomerase holoenzyme adds telomeric DNA repeats at the termini of eukaryotic chromosomes, thus maintaining telomere length and function despite telomere attrition that normally occurs during chromosomal replication. Telomeric DNA repeats and specific associated proteins are assembled to form telomere structures that distinguish normal chromosome ends from DNA damage-induced double-strand breaks and thus subserve a critical function in maintaining chromosomal stability (1-3). The functional importance of telomere integrity and telomerase activity has been addressed in a variety of experimental model systems, notably including genetic alterations of telomerase and telomeric proteins in multiple eukaryotic species. Evidence for a physiologically important role of telomerase in humans first emerged from analysis of the genetic syndrome dyskeratosis congenita (DKC), characterized by failure of bone morrow and other rapidly dividing cell lineages. An X-linked form of DKC was the first human disease recognized to be related to telomerase deficiency and is c...

A non-genetic, epigenetic-like mechanism of telomere length inheritance?

“…Therefore, this indicates that a subject's TL at least partially reflects the TL of his/her parents' specific germ cells. Note that this direct mechanism, which is also supported by studies in mice, 9 is indeed straightforward and has been suggested before by us and others. 8,10 However, it is an unlikely mechanism in case of X-linked or paternal inheritance.…”

Spermatozoa telomeres determine telomere length in early embryos and offspring

“…However, in the latter case, we acknowledge that although the differences observed at the two-cell stage are only dependent on spermatozoa TL, the differences observed later, after the onset of embryonic telomerase expression, may have been influenced by possible differences in activity or expression between Mus musculus and Mus spretus telomerases. Further support for the major role of spermatozoa TL in offspring TL comes from a study of TERT haploinsufficiency in mice, where the restoration of TERT was not able to restore TL in the offspring, thereby suggesting that other factors, such as sperm TL, determined the offspring TL (Chiang et al 2010). …”

Maternal telomere length inheritance in the king penguin

“…We could hypothesize that the pattern of telomere length heredity is dependent on the inheritance pattern of multiple telomere length restoration/maintenance factors (Blackburn, 2001;Blasco, 2007b). A resetting mechanism of early-life telomere length has been pointed out in mammals, in which both telomerase activity and parent telomere length are interacting to set-up the embryo starting telomere length (Chiang et al, 2010). Focusing on these processes in the future might enable us to better understand how progressive telomere shortening over generations is avoided and how interspecific variability in telomere dynamics may have evolved.…”