Severe sepsis results in modulated chromatin modifying enzyme expression in bone marrow resident hematopoietic stem cells (121.15)

Abstract

Abstract Uncontrolled inflammatory responses drive the high mortality observed in severe sepsis and septic shock. Paradoxically, survivors of severe sepsis exhibit profound cellular immunosuppression, resulting in increased susceptibility to secondary, opportunistic and nosocomial infections. Recent studies have identified epigenetic repression of genes in peripheral immune cells post-sepsis as one possible mechanism underlying this immunosuppression. As post-septic immunosuppression can manifest long after recovery from sepsis, it was hypothesized that any observed epigenetic regulation of pro-inflammatory genes may also occur in hematopoietic stem cells, and in turn, these changes would be due to the up- or down-regulation of chromatin modifying enzymes (CMEs). Superarray analysis of mRNA isolated from CD117+ hematopoietic stem cells isolated from animals subjected to an experimental model of sepsis identified a distinct set of modulated mRNAs encoding distinct histone modifying enzymes - including methyltransferases (Dot1l, Prmt8 and Smyd1) and demethylases (Kdm5b), among others. These results indicate that severe sepsis can modulate the expression of CMEs in hematopoietic stem cells, suggesting distinct changes in the epigenetic signature of these cells. As these CMEs are associated with distinct histone modifications, these results can be used to guide further investigations into the genes targeted by these distinct epigenetic marks.