Alternative polyadenylation links RNA processing to iron metabolism in human erythropoiesis

Alternative polyadenylation (APA), a post-transcriptional mechanism generating mRNA isoforms with varying 3' UTR lengths, regulates mRNA stability, localization, and translation. CPSF6 is a core subunit of the cleavage factor Im (CFIm) complex, a critical 3' end processing machinery that recognizes UGUA motifs to mediate downstream PAS selection. Here, we report widespread APA regulation during erythropoiesis, and demonstrate that CPSF6 plays a key role in this process through its regulation of APA. Knockdown of CPSF6 significantly impairs erythropoiesis and leads to dramatic 3' UTR shortening, including genes related to iron metabolism, accompanied by changes in their RNA expression levels.