Functional sequestration of transcription factors by junk DNA

Higher eukaryote genomes contain repetitive DNAs concentrated in transcriptionally inactive heterochromatin. These ‘junk’ DNAs seldom are considered as direct contributors to gene expression. However, some transcription factors can bind repetitive elements in vitro and Drosophila embryos treated with drugs that disrupt transcription factor binding to a repetitive element undergo homeotic transformations. Here we demonstrate that binding to mouse major α‐satellite repetitive DNA by CCAAT/Enhancer Binding Protein alpha (C/EBPα) functionally sequesters C/EBPα in pericentromeric heterochromatin. C/EBPα binding to α‐satellite DNA was inhibited by an altered‐specificity mutation that results in poor binding to α‐satellite DNA but normal binding to some C/EBPα sites in gene promoters, or by co‐expression of the transcription factor Pit‐1. Both treatments elevated C/EBPα concentration in the non‐heterochromatic subcompartment of the cell nucleus, resulting in enhanced promoter binding and gene activation by C/EBPα. Thus, binding sites in repetitive DNA titre the amount of C/EBPα available for promoter binding and transcription regulation. Models of gene regulation may need to consider the consequences of pan‐genomic transcription factor “buffering” arising through competition between far distant genomic sites.