Key Points Increase in HDAC binding is required for HDAC inhibitors to enhance gene transcription. G6PD deficiency in erythroid precursors can be restored by HDAC inhibitor-mediated increased transcription of the variant gene.

How the transcription repressing complex Polycomb interacts with transcriptional regulators at housekeeping genes in somatic cells is not well understood. By exploiting a CpG island (CGI) point mutation causing a Mendelian disease, we show that DNA binding of activating transcription factor (TF) determines histone acetylation and nucleosomal depletion commensurate with Polycomb exclusion from the target promoter. Lack of TF binding leads to reversible transcriptional repression imposed by nucleosomal compaction and consolidated by Polycomb recruitment and establishment of bivalent chromatin status. Thus, within a functional hierarchy of transcriptional regulators, TF binding is the main determinant of Polycomb recruitment to the CGI of a housekeeping gene in somatic cells.

Key Points B cells but not red cells are GPI deficient in PIGM-associated IGD, caused by a core promoter mutation that abrogates Sp1 binding. In red but not B cells, PIGM transcription is independent of Sp1 binding to the core promoter, hence GPI expression in red cells is near normal.