Extensive binding of poorly characterized human transcription factors to genomic dark matter

The functional impact of a large portion of the human genome known as "dark matter DNA", which is composed mainly of repeat sequences, remains unknown. The genome also encodes many putative and poorly characterized transcription factors. Here, we determine genomic binding locations of 166 poorly characterized human transcription factors in living cells. Nearly half of them associate strongly with known regulatory regions such as promoters and enhancers, frequently co-localizing with each other at conserved motif matches. The other half often associate with genomic dark matter, however, at largely non-overlapping (i.e., unique) sites, via intrinsic sequence recognition. Fifty-four of the latter half, which we term dark transcription factors, mainly bind within regions of closed chromatin, with each recognizing a unique set of repeat sequences. The dark transcription factors include many KZNFs, which are known to bind and silence transposable elements, and other transcription factors with apparent repressive functions. Others may be pioneer transcription factors. For example, we find that induction of TPRX1, a known regulator of zygotic preimplantation, leads to chromatin opening at many of its binding sites in the dark matter genome.