The lifespan quantitative trait locus gene Securin controls hematopoietic progenitor cell function

Abstract

The percentage of murine hematopoietic stem and progenitor cells, which present with a loss of function upon treatment with the genotoxic agent hydroxyurea, is inversely correlated to the mean lifespan of inbred mice, including the long-lived C57BL/6 and short-lived DBA/2 strains. Quantitative trait locus mapping in BXD recombinant inbred strains identified a region spanning 12.5 cM on the proximal part of chromosome 11 linked to both the percentage of dysfunctional hematopoietic stem and progenitor cells as well as regulation of lifespan. By generating and analyzing reciprocal congenic mice for this locus, we demonstrate that this region indeed determines the sensitivity of hematopoietic stem and progenitor cells to hydroxyurea. These cells do not present, as previously anticipated, with differences in cell cycle distribution, and also not with changes in the frequency of cells undergoing apoptosis, senescence, replication stalling and re-initiation activity, excluding that variations in proliferation, replication or viability underlie the distinct response of these cells from the congenic and parental strains. An epigenetic aging clock in blood cells was accelerated in C57BL/6 mice congenic for the DBA/2 version of the locus. We verified pituitary tumor-transforming gene-1 (Pttg1)/Securin as the quantitative trait gene regulating the differential response of hematopoietic stem and progenitor cells to hydroxyurea treatment and which might thus likely be linked to the regulation of lifespan.

Epigenetic age-predictions in mice using pyrosequencing, droplet digital PCR or barcoded bisulfite amplicon sequencing

“…We have previously demonstrated, that epigenetic age-predictions with our 3 CpG pyrosequencing agepredictor are accelerated in DBA/2 mice, as compared to C57BL/6 mice, which may reflect the different life expectancy of these mouse strains (Han et al, 2018). Furthermore, we demonstrated that age-predictions with this predictor were also accelerated in C57BL/6 mice with quantitative trait locus insertion from DBA/2 into the congenic C57BL/6 chromosome 11, which was expected to be associated with the shorter lifespan of DBA/2 (referred to as Line A mice) (Brown et al, 2019). We now determined, within the same samples, whether the epigenetic age-acceleration can also be observed in DBA/2 mice (n = 33) and Line A mice (n = 15) using the BBA-seq approach.…”

“…For epigenetic age predictions we either used (a) the 3 CpG multivariable model, or (b) the lasso regression model based on 7 CpGs of the same three amplicons (Prima1, Hsf4, Kcns1). As previously described for pyrosequencing, epigenetic age-predictions were logarithmically accelerated in DBA/2 mice (Han et al, 2018), and also accelerated in Line A mice (Brown et al, 2019).…”

“…In fact, the predictions with either the 3 CpG BBA-seq, or the 7 CpG BBA-seq Lassoregression model, provided very similar results as previously observed for the 3 CpG pyrosequencing clock (Figure 5a and b). DNAm levels were analyzed with BBA-seq in blood samples of 40 C57BL/6 mice of the validation sets, 33 DBA/2 mice, and 15 transgenic C57BL/6 mice with an age-associated region from DBA/2 mice (Line A) (Brown et al, 2019). For epigenetic age predictions we either used (a) the 3 CpG multivariable model, or (b) the lasso regression model based on 7 CpGs of the same three amplicons (Prima1, Hsf4, Kcns1).…”

“…We have recently described an epigenetic clock that is based on pyrosequencing of DNAm at only three age-associated CpGs to facilitate a high accuracy with chronological age in C57BL/6 mice (Han et al, 2018). Notably, epigenetic aging was significantly accelerated in the shorter-lived DBA/2 mice (Han et al, 2018), and in congenic C57BL/6 mice harboring regions of chromosome 11 from DBA/2 mice that is likely linked to the regulation of lifespan (referred to as Line A mice) (Brown et al, 2019). The epigenetic age was also decelerated by systemic administration of a drug that extended murine lifespan (Florian et al, Accepted for publication), implying that the three CpGs might also serve as biomarkers of aging at least on an C57BL/6 background.…”

Targeted methods for epigenetic age predictions in mice

“…We have recently described an epigenetic clock that is based on pyrosequencing of DNAm at only three age-associated CpGs to facilitate a high accuracy with chronological age in C57BL/6 mice 17 . Notably, epigenetic aging was significantly accelerated in the shorter-lived DBA/2 mice 17 , and in congenic C57BL/6 mice harboring regions of chromosome 11 from DBA/2 mice likely linked to the regulation of lifespan (referred to as Line A mice) 18 . The epigenetic age was also decelerated by systemic administration of a drug that extended murine lifespan 19 , implying that the three CpGs might also serve as biomarkers of aging at least on an C57BL/6 background.…”