INO80 requires a polycomb subunit to regulate the establishment of poised chromatin in murine spermatocytes

INO80 is the catalytic subunit of the INO80-chromatin remodeling complex that is involved in DNA replication, repair and transcription regulation. 1no80 deficiency in murine spermatocytes (Ino80c(KO) results in pachytene arrest of spermatocytes due to incomplete synapsis and aberrant DNA double-strand break repair, which leads to apoptosis. RNA-seq on ino80c(KO) spermatocytes revealed major changes in transcription, indicating that an aberrant transcription program arises upon INO80 depletion. In ino80(WT) spermatocytes, genome-wide analysis showed that INO80-binding sites were mostly promoter proximal and necessary for the regulation of spermatogenic gene expression, primarily of premeiotic and meiotic genes. Furthermore, most of the genes poised for activity, as well as those genes that are active, shared INO80 binding. In ino80c(KO) spermatocytes, most poised genes demonstrated de-repression due to reduced H3K27me3 enrichment and, in turn, showed increased expression levels. INO80 interacts with the core PRC2 complex member SUZ12 and promotes its recruitment. Furthermore, INO80 mediates H2A.Z incorporation at the poised promoters, which was reduced in Ino80c(KO) spermatocytes. Taken together, IN080 is emerging as a major regulator of the meiotic transcription program by mediating poised chromatin establishment through SUZ12 binding.

Automated summary

INO80 is a catalytic subunit involved in DNA replication, repair, and transcription regulation. Its deficiency in murine spermatocytes leads to apoptosis and abnormal transcription. INO80 binding is primarily located near the promoter region and is necessary for the regulation of spermatogenic gene expression. In the absence of INO80, genes that were poised for activation become derepressed and show increased expression levels.