Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance

Abstract

The (histone) deacetylase Sirt1 is a mediator of genomic and epigenetic maintenance, both of which are critical aspects of stem cell homeostasis and tightly linked to their functional decline in aging and disease. We show that Sirt1 ablation in adult hematopoietic stem and progenitor cells (HSPCs) promotes aberrant HSPC expansion specifically under conditions of hematopoietic stress, which is associated with genomic instability as well as the accumulation of DNA damage and eventually results in a loss of long-term progenitors. We further demonstrate that progenitor cell expansion is mechanistically linked to the selective upregulation of the HSPC maintenance factor and polycomb target gene Hoxa9. We show that Sirt1 binds to the Hoxa9 gene, counteracts acetylation of its histone target H4 lysine 16, and in turn promotes polycomb-specific repressive histone modification. Together, these findings demonstrate a dual role for Sirt1 in HSPC homeostasis, both via epigenetic regulation of a key developmental gene and by promoting genome stability in adult stem cells.

Stem cells and the impact of ROS signaling

“…These results show that communication between the nucleus and mitochondria mediated by NAD is crucial for decelerating the ageing process. In this context, recent findings implicating SIRT proteins in the regulation of blood stem cells and their ageing are notable (Brown et al, 2013;Rimmelé et al, 2014;Singh et al, 2013). Although SIRT3 is critical for the maintenance of the blood stem cell pool in old mice or under stress, SIRT1 is key to the maintenance of blood stem cells in young adult mice during both steady-state and stress conditions (Brown et al, 2013;Rimmelé et al, 2014;Singh et al, 2013).…”

“…In this context, recent findings implicating SIRT proteins in the regulation of blood stem cells and their ageing are notable (Brown et al, 2013;Rimmelé et al, 2014;Singh et al, 2013). Although SIRT3 is critical for the maintenance of the blood stem cell pool in old mice or under stress, SIRT1 is key to the maintenance of blood stem cells in young adult mice during both steady-state and stress conditions (Brown et al, 2013;Rimmelé et al, 2014;Singh et al, 2013). Loss of SIRT1 results in an ageing-like phenotype associated with defective lineage specification, as well as other hallmarks of stem cell ageing, including the accumulation of ROS and DNA damage in young adult mice, some of which is mediated by relative loss of FOXO3 activity in the Sirt1 mutant HSC (Rimmelé et al, 2014).…”

“…Hydroxyvalines and hydroxyleucines are common markers in advanced stages of human diseases, such as atherosclerosis. SIRT1 and TET enzymes are crucial factors in regulating hematopoietic stem cells (Moran-Crusio et al, 2011;Rimmelé et al, 2014;Singh et al, 2013). However, how flux through various metabolic pathways and nutrient availability control the concentrations of substrates required by histone-modifying enzymes has not yet been fully explored in stem cells.…”

“…As well as a role in redox regulation, ROS might also function to alter the epigenetic landscape, which plays a particularly pertinent role in regulating stem cell fate (Challen et al, 2012;Mishra et al, 2014;Rimmelé et al, 2014;Singh et al, 2013;Trowbridge et al, 2009;. Many metabolic intermediates are necessary substrates for the post-translational modifications of histones that together establish the epigenetic landscape of stem cells.…”

Epigenetics of hematopoietic stem cell aging and disease

“…Significantly reduced [47,48] Sirt1 Loss of Sirt1 causes expansion of HSPCs under conditions of hematopoietic stress, which results in increased accumulation of DNA damage and exhaustion of HSCs in mice [51] Sirt3 is downregulated with aging [53] Sirt3 Overexpression of Sirt3 improves the regenerative capacity of aged HSCs [53] suggestive of their role in HSC aging [40][41][42][43]. Despite this growing body of evidence supporting the role of PcG complexes in HSC aging, we still do not know how changes in PcG complex activity contribute to HSC aging other than by its impact on the Ink4a/Arf locus.…”