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Trepel, J.

Publications and source records attributed to Trepel, J..

2 recordsLinked to original sources

Trade-offs beget trade-offs: Causal analysis of mammalian population dynamics

Survival and reproduction strategies in mammals are determined by trade-offs between life history traits. In turn, the unique configuration of traits that characterize mammalian species give rise to species-specific population dynamics. The dependence of population dynamics on life history has been primarily studied as the relationship between population density and size-related traits. With the recent accumulation of genomic data, the effective population size (Ne) over million-year timescales has become quantifiable for a large proportion of mammal species. Using phylogenetic path analysis, we compared the dependence of population density and Ne on eleven traits that characterize mammalian allometry, diet and reproduction. We found variable impacts of traits on the two metrics of population dynamics across different classifications of mammalian species. For example, we found a negative association between brain size and both population density and Ne overall, but brain size was positively associated with Ne in carnivorans. Dietary specialization had a negative effect on population density, especially in ungulates. Ne of ungulates and primates was strongly affected by time to maturity and weaning age, respectively, highlighting the difference in reproductive strategy between these orders. The relationship between Ne and adult mass showed a gradient in association strength from cold to warm biomes. Together, our findings demonstrate that trade-offs not only characterize life-history evolution, but also extend across different metrics of population dynamics and vary among species groups. This challenges the static nature of the "energetic equivalence" rule and has major implications for selecting appropriate metrics for species conservation and restoration strategies.

evolutionary biology↗

HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.

biochemistry↗