1003 – ESTABLISHING SAMD1-DEPENDENT ACTIVITIES IN HEMATOPOIESIS AND ERYTHROPOIESIS

Transitions between cell progenitors and progeny depend on precise transcriptional mechanisms to adjust gene expression programs. The sterile alpha motif-containing 1 (SAMD1) gene encodes a transcription factor which coordinates histone modifications during embryonic stem cell exit from pluripotency. SAMD1 is expressed throughout many biological systems, but its role in hematopoiesis is unknown. SAMD1 prefers to bind chromatin at unmethylated CpG islands (CGIs), where it acts primarily as a transcriptional repressor. SAMD1 interacts with and promotes the function of lysine demethylase LSD1, which blocks terminal erythropoiesis. Samd1 knockout is embryonic lethal in mice. To test Samd1 in hematopoiesis, we performed competitive transplant experiments in mice using shRNA knockdown HSCs. Samd1 knockdown versus control HSCs revealed an increase in HSC repopulation with 3.9-fold more CD45.2+ after 8 weeks. We conducted scRNA-seq and chromatin occupancy profiling in Samd1 knockdown and knockout cells, revealing that Samd1 regulated a genetic network consistent with a role in stem cell self-renewal, including the repression of erythroid-specific genes. Ongoing experiments are testing whether SAMD1 functions in partnership with the lysine demethylase LSD1 during erythropoiesis. Both SAMD1 and LSD1 are commonly upregulated in acute myeloid leukemia (AML), and high expression is correlated with poor prognosis. These mechanisms may be exploitable to improve HSC expansion ex vivo. Linking Samd1 function to signaling, transcription, or other cellular functions opens the door to translational avenues for studying the contribution of Samd1 in hematologic pathologies.