The SAMD1 transcription factor coordinates hematopoietic lineage differentiation and H3K4 methylation status [RNA-seq]

Cell progenitor to progeny transitions depend on precise transcriptional mechanisms to adjust gene expression. The sterile alpha motif-containing 1 protein (SAMD1) regulates a shift in transcriptional activity during embryonic stem cell exit from pluripotency. SAMD1 interacts with and facilitates the activity of the histone H3 lysine demethylating enzyme LSD1. SAMD1 is expressed throughout many biological systems, but its role in hematopoiesis is unknown. In human and mouse hematopoietic stem/progenitor cells, we tested the role of SAMD1 in hematopoiesis and erythropoiesis using loss-of-function approaches. We discovered that SAMD1 promotes expression of critical drivers of hematopoiesis, including the GATA2 transcription factor, while opposing erythroid programs. Loss of SAMD1 in ex vivo differentiating cells increased erythroid differentiation and altered the landscape of histone H3K4 methylation genome-wide. Cohorts of SAMD1-repressed genes are linked to erythropoietic activities. SAMD1 expression promoted ERK signaling via SCF/Kit stimulation in progenitor populations. In erythroid precursor cells, SAMD1 co-occupies chromatin with LSD1 and GATA factors. Whereas SAMD1 downregulates H3K4me2 levels genome-wide, contributing to gene repression, SAMD1 elevates transcription at select sites. To test Samd1 function in hematopoiesis, we performed competitive transplant experiments in mice using shRNA knockdown HSCs. Samd1 knockdown contributed more to peripheral blood mononuclear cells versus control HSCs. Our results establish SAMD1 as a coordinator of H3K4 methylation and stem/progenitor activity in hematopoiesis and erythropoiesis.