The AI model Geneformer helped identify Pbx1 as a gene that alters early blood recovery in mice

The AI model Geneformer helped identify Pbx1 as a gene that alters early blood recovery in mice

In an article published on 21 August in Science Advances, researchers combined an AI model with data on gene activity in individual blood stem cells, experimental screening of genetic regulators, and cell transplantation in mice. This approach allowed them to trace how Pbx1 contributes to an age-related shift: after transplantation, old cells restore red blood cells less effectively and produce platelet precursors more often.

Hematopoietic stem cells (HSC) replenish blood cells throughout life. When they begin restoring blood after transplantation, old HSC produce cells of the megakaryocytic lineage, which are platelet precursors, more often and restore red blood cells less effectively. The authors found two related programs in old HSC: features of the least differentiated state and a shift toward producing cells of the platelet lineage. They sought a genetic regulator that links these changes.

The team fine-tuned Geneformer, an AI model that identifies the state of an individual cell from its combination of active genes, using ten datasets from young and old mouse HSC. In a virtual experiment, the model simulated increased activity of each gene and assessed whether this made a young HSC resemble an old one. Increasing Pbx1 activity was one of the interventions that shifted young cells in this direction.

The researchers then tested this prediction in cells. They increased the activity of 143 regulators of gene expression associated with hematopoiesis, one at a time, in young HSC and monitored CD48, a marker of the transition from a stem cell to more specialized progenitors. Increasing Pbx1 activity delayed the appearance of CD48, and Pbx1 activity was higher in old HSC. In young cells with increased Pbx1 activity, part of the age-related gene program became active, while the accessibility of some DNA regions to transcription changed.

One of the tested pathways led to Gata1, a gene that initiates red blood cell formation. When Pbx1 activity was increased, Gata1 activation was weaker. Two weeks after transplantation into mice, young HSC with increased Pbx1 activity restored red blood cells less effectively, while platelet production was maintained. Suppressing Pbx1 in old HSC reduced the bias toward platelet production and also reduced red blood cell recovery.