The overall goal of our research is to investigate molecular mechanisms of aging in hematopoietic stem cells (HSCs). Hematopoiesis requires high levels of cellular regeneration, including the production of billions of platelets, erythrocytes and immune cells on a daily basis. HSC function declines with age, a process that has been implicated in the rise of infections, cancers, rheumatoid, and cardiovascular diseases. Molecular changes during aging, especially those involving genetic and epigenetic mechanisms are being investigated by several groups. These pathways mostly impact de novo transcription of genes. In contrast, little is known about changes affecting the post-transcriptional fate of mRNA during aging. To better understand the role of mRNA decay, we investigated the poly-A binding protein C1 (PABPC1), a key regulator of transcript turnover in the cytosol. We found a novel interaction between the prolyl-isomerase cyclophilin A and PABPC1. Our data suggest that cyclophilin A alters the structure of PABPC1 to facilitate mRNA elimination. Depletion of cyclophilin A stabilizes transcripts by slowing mRNA decay. To study the impact of mRNA turnover on hematopoiesis, we performed a suite of functional assays using cyclophilin A-deficient mice. HSCs lacking the prolyl-isomerase display the hallmarks of aging, including increased cell division, myeloid skewing, and stem cell exhaustion. Importantly, gene expression profiling revealed that cyclophilin A deficiency and native aging share similar changes to the transcriptome. In cells lacking cyclophilin A, these are caused by reduced mRNA decay. Moreover, we provide evidence that mRNA turnover is also slowing down in physiologically aged hematopoietic cells. Based on this evidence, we hypothesize that reduced mRNA decay rates in aged HSCs alter the transcriptome and that these changes promote aging in the hematopoietic compartment. We will formally test this hypothesis using molecular, cellular, and newly developed in vivo models. Specifically, we will (A) quantify mRNA levels and mRNA turnover in HSCs during aging, (B) investigate molecular causes for altered mRNA decay in old cells, and (C) determine whether delayed mRNA clearance contributes to oligoclonality with age. Successful implementation of these aims will further our understanding of the post-transcriptional changes that shape hematopoietic stem cell aging. Focusing on the dynamics of mRNA turnover will add a conceptually novel dimension to existing work on gene transcription in the hematopoietic system.
Aging blood stem cells have been implicated in cancers, cardiovascular diseases, and infections. These diseases represent the leading causes of death in the US and warrant more detailed studies of the defects within aged blood stem cells. In this study, we will investigate a novel mechanism that induces changes to gene patterns and determine how this process promotes aging of blood stem cells.
| Catic, Andre (2018) Cellular Metabolism and Aging. Prog Mol Biol Transl Sci 155:85-107 |
