Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation

Histones shape chromatin structure and the epigenetic landscape. H1, the most diverse histone in the human genome, has 11 variants. Due to the high structural similarity between the H1s, their unique functions in transferring information from the chromatin to mRNA-processing machineries have remained elusive. Here, we generated human cell lines lacking up to five H1 subtypes, allowing us to characterize the genomic binding profiles of six H1 variants. Most H1s bind to specific sites, and binding depends on multiple factors, including GC content. The highly expressed H1.2 has a high affinity for exons, whereas H1.3 binds intronic sequences. H1s are major splicing regulators, especially of exon skipping and intron retention events, through their effects on the elongation of RNA polymerase II (RNAPII). Thus, H1 variants determine splicing fate by modulating RNAPII elongation.The research was funded by the Israel Science Foundation (ISF 671/18, ISF 142/13, and ISF 2417/20); the Israel Cancer Research Foundation (ICRF PG-18-105, PG-20-104); and the United States – Israel Binational Science Foundation (BSF 2017086). V.R.R. was supported by Edmond J. Safra Bioinformatics Center fellowship at Tel Aviv University.Peer reviewe