Biology subjects

Yellan, I.

Publications and source records attributed to Yellan, I..

2 recordsLinked to original sources

bioRxiv2024

Perspectives on Codebook: sequence specificity of uncharacterized human transcription factors

Gene expression is regulated by transcription factors (TFs), which recognize specific DNA sequence motifs. Several hundred putative human TFs, identified mainly by an apparent DNA-binding domain, lack known binding motifs1, and even for well-characterized TFs, it remains controversial to what degree motifs accurately reflect binding sites in living cells2,3. Here, we describe a systematic effort ("Codebook") to determine the sequence specificity of 332 putative and poorly characterized human TFs. Over 4,000 independent experiments, encompassing multiple in vitro and in vivo assays, produced motifs for just over half (177, or 53%), of which most are unique to a single protein, thereby extending the vocabulary of sequence recognition encoded by human TFs by [~]100 distinct motifs. Moreover, binding motifs identified in vitro are strongly enriched within cellular binding sites. Collectively, the data reveal tens of thousands of previously unknown, conserved, and direct TF binding sites across the human genome. These sites are concentrated in promoter regions, and are predictive of gene expression, illustrating that this new data atlas provides an important step forward in decoding the human genome.

genomics↗

bioRxiv2024

Extensive binding of uncharacterized 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 enigmatic. The genome also encodes hundreds of putative and poorly characterized transcription factors (TFs). Here, we determined genomic binding locations of 166 poorly characterized human TFs 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 TFs", mainly bind within regions of closed chromatin, with each recognizing a unique set of repeat sequences. The Dark TFs include many KZNFs, which are known to bind and silence TEs, and other TFs with apparent repressive functions. By contrast, some may be pioneers: 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. Altogether, our results shed light on a large fraction of poorly characterized human TFs and simultaneously illuminate the diversity of function within the dark matter genome.

genomics↗