Role of ST6Gal-1 sialyltransferase in inflammation and hematopoiesis

The ST6Gal-1 sialyltransferase is expressed abundantly in liver where it's expression is mediated by the P1 promoter, one of the six known distinct promoter-regulatory region of ST6Gal-1 gene. Hepatic ST6Gal-1 contributes to alpha2,6-sialylation of liver-derived serum glycoproteins as well as the pool of ST6Gal-1 released into systemic circulation. In this study we demonstrated that mutant mice with ST6Gal-1 deficiency exhibit greater Th1 and Th2 inflammatory responses with an exaggerated granulocyte number and a greater pool of proliferative myeloid cells. We further showed that this phenotype is associated specifically with the disruption of P1 promoter. Siat1DeltaP1 mice with specific disruption to the P1 region have a significantly altered hematopoietic compartment, including an inflated population of hematopoietic stem and progenitor cells. Hematopoietic stem and progenitor cells of Siat1DeltaP1 mice are at a more actively cycling state and display faster proliferation and differentiation. The P1 promoter was not active in hematopoietic stem and progenitor cells, nor was it active in the stromal cells of the bone marrow, strongly suggesting that the altered hematopoietic compartment resulted from extra-medullary sources, putatively from the liver. Our data points to a novel pathway where ST6Gal-1 released into circulation can regulate hematopoiesis, and there is an inverse relationship between the level of extrinsic ST6Gal-1 and the proliferation and differentiation of hematopoietic stem and early progenitor cells.