Extensive binding of uncharacterized human transcription factors to genomic dark matter

Most of the human genome is thought to be non-functional, and includes large segments often referred to as “dark matter”. The genome also encodes hundreds of putative transcription factors (TFs) that lack known DNA binding motifs and are poorly characterized. We determined genomic binding locations of 166 uncharacterized human TFs in living cells. Nearly half of them associated strongly with known regulatory regions such as promoters and enhancers, often at conserved motif matches and co-localizing with each other. Surprisingly, the other half often associated with genomic dark matter, at largely unique sites, via intrinsic sequence recognition. Dozens of these, which we term “Dark TFs” mainly bind within regions of closed chromatin. Dark TF binding sites are more rarely under purifying selection, and are enriched for transposable elements. Many are KZNFs, which contain the repressive KRAB domain, but many are not, and may represent potential pioneer TFs: based on compiled literature information, the Dark TFs exert diverse functions ranging from early development to tumor suppression. Thus, a large fraction of uncharacterized human TFs may function in previously unappreciated aspects of the dark matter genome. This accession contains the Chromatin Immunoprecipitation raw data for this study. It is associated with derivative data located in the Gene Expression Omnibus database under accession GSE280248. The article used also data derived from High Throughput SELEX and Genomic High throughput SELEX that are available under accessions: PRJEB61115 and PRJEB76622, respectively.