Publicly available data sequence data generated as part of this study (naRNA-seq and H3K36ME3 Cut&Tag) is publicly available and has been deposited in Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/) under accession GSE252006. Other publicly data utilized in this study included genotypes were downloaded from the 1000 Genomes project (http://ftp.1000genomes.ebi.ac.uk/vol1/ftp/data_collections/1000G_2504_high_coverage/). FASTQ files of short-read RNA-seq data of shRNA dKD of SMG6 and SMG7 in HeLa cells and shRNA controls from a previous study (SRA accession SRP083135) are available at https://www.ncbi.nlm.nih.gov/sra. Other publicly available short-read sequencing data are described in Supplementary Fig. 1. For these datasets, we obtained FASTQ files of standard short-read RNA-seq data from the following accession numbers: ENA project accession PRJEB3365 (steady-state RNA-seq produced by the GEUVADIS consortium), SRA project accession PRJNA268086 (H3K4me1, H3K4me3 and H2K27ac ChIP-seq) and SRA project accession PRJNA302818 (4sU RNA-seq). The 3′ sequencing APA data were obtained as a sample by peak expression matrix from authors of a previous study (SRA accession number SRP223759). The data were aligned to GRCh38 and transcript release v34 annotations from Gencode (https://www.gencodegenes.org/human/). Some analyses (Supplementary Methods) also utilized v37 annotations.

Pipelines and all original code are available at Zenodo via https://doi.org/10.5281/zenodo.12571961 (ref. 85) and also at Github via https://github.com/bfairkun/ChromatinSplicingQTLs/.

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