The processing of the proximal and distal poly(A) sites in alternative polyadenylation (APA) has long been thought to independently occur on pre-mRNAs during transcription. By Fractionation-seq, we unexpectedly identified several hundred APA genes where their distal polyA isoforms are retained in chromatin/nuclear matrix and proximal polyA isoforms are released into the cytoplasm. Global metabolic PAS-seq and Nanopore long-read RNA-seq provided further evidence that the strong distal polyA sites are first processed and the resulting transcripts are anchored in chromatin/nuclear matrix to serve as precursors for further processing at proximal polyA sites. By inserting an autocleavable ribozyme between the proximal and distal polyA sites, coupled with the newly developed Cleave-seq, we demonstrated that the distal polyA isoform is indeed the precursor to the proximal polyA isoform. The proximal sites for many genes could be activated sequentially following the distal ones — sequential polyadenylation, providing a versatile strategy to regulate gene expression in mammalian cells. I will review the established mechanisms for APA regulation and then discuss the additional insights into APA regulation from the perspective of sequential polyadenylation, resulting in a unified leverage model for understanding the mechanisms of regulated APA.