A newly identified gene Ahed plays essential roles in haematopoiesis through RNA splicing

Abstract The development of haematopoiesis is regulated by coordinated actions of multiple genes. Mutations in some genes are intimately involved in the occurrence of haematological cancers. Here, we report a previously undefined functional gene in haematopoiesis, which we isolated by screening mutant embryonic stem cells. The gene, named “ attenuated haematopoietic development ” ( Ahed ), encoded an uncharacterized nuclear protein. We found that Ahed conditional knock out (cKO) foetuses became anaemic after E14.5 and died before birth. Transplantation experiments revealed that Ahed -deficient lineage - Sca-1 + c-Kit Hi cells were unable to reconstitute haematopoiesis in vivo , suggesting that Ahed is indispensable for functional haematopoietic stem/progenitor cells. Multiple RNA sequencing analyses of Ahed -cKO cells revealed that this protein governs various critical pathways by regulating alternative splicing of RNAs. Published databases of cancer-related mutations present blood cancer patients with somatic mutations in the Ahed gene. Thus, Ahed plays a fundamental role in haematopoiesis through RNA splicing, whose mutations relates to malignancies.