Nudt21 controls cell fate by connecting alternative polyadenylation to chromatin signaling

Cell fate transitions involve rapid changes of gene expression patterns and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we used transcription-factor induced reprogramming of somatic cells into pluripotent cells to screen for novel regulators of cell fate change. We identified the RNA processing factor Nudt21, a component of the pre-mRNA cleavage and polyadenylation complex, as a potent barrier to reprogramming. Importantly, suppression of Nudt21 not only enhanced the generation of induced pluripotent stem cells but also facilitated the conversion of fibroblasts into trophoblast stem cells and delayed the differentiation of myeloid precursor cells into macrophages, suggesting a broader role for Nudt21 in controlling cell fate change. Polyadenylation site sequencing (PAS-seq) revealed that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency. While only a fraction of these transcripts changed expression at the protein level, this fraction was strongly enriched for chromatin regulators, including components of the PAF, Polycomb, and Trithorax complexes. Co-suppression analysis further suggests that these chromatin factors are potent mediators of reprogramming, providing a mechanistic basis for our observations. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of mammalian cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling. Overall design: Examination of the chromatin accessibility landscape by ATAC-seq during OSKM-mediated reprogramming of MEFs, transfected with siRNAs targeting Nudt21 or control siRNAs, into iPSCs at distinct time-points during the reprogramming process.