2026-08-26 スイス連邦工科大学ローザンヌ校(EPFL)
＜関連情報＞
- https://actu.epfl.ch/news/cracking-the-code-of-gene-regulation/
- https://www.nature.com/articles/s41586-026-10798-9
- https://www.nature.com/articles/s41467-026-71387-y
ヒト転写因子のDNA結合特異性に関する拡張コードブック An expanded codebook of human transcription factor DNA-binding specificity
Arttu Jolma,Kaitlin U. Laverty,Ali Fathi,Ally W. H. Yang,Isaac Yellan,Ilya E. Vorontsov,Antoni J. Gralak,Judith F. Kribelbauer-Swietek,Sachi Inukai,Rozita Razavi,Mihai Albu,Alexander Brechalov,Zain M. Patel,Vladimir Nozdrin,Georgy Meshcheryakov,Andrey Buyan,Ivan Kozin,Sergey Abramov,Alexandr Boytsov,The Codebook Consortium,Quaid Morris,Matthew T. Weirauch,Oriol Fornes,Vsevolod J. Makeev,… Timothy R. Hughes
Nature Published:05 August 2026
DOI:https://doi.org/10.1038/s41586-026-10798-9
Abstract
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. Furthermore, even for well-characterized TFs, it remains controversial the degree to which motifs accurately reflect binding sites in living cells2. Here we describe a systematic effort (‘Codebook’) to determine the sequence specificity of 332 putative and poorly characterized human TFs. More than 4,000 independent experiments, encompassing multiple in vitro and in vivo assays, produced motifs for just over half (177; 53%) of the TFs, of which most are associated with only a single protein. These results extend the vocabulary of sequence recognition encoded by human TFs by around 130 distinct motifs. Moreover, binding motifs identified in vitro are strongly enriched in 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. In summary, this new codebook provides an important step forward in decoding the human genome.
meSMiLE-seqを用いたメチル化感受性ヒト転写因子の同定Identification of methylation-sensitive human transcription factors using meSMiLE-seq
Antoni J. Gralak,Katerina Faltejskova,Ally W. H. Yang,Clemence Steiner,Julie Russeil,Nadia Grenningloh,Sachi Inukai,Mustafa Demir,Riccardo Dainese,Cooper Owen,Eugenia V. Pankevich,Codebook/GRECO-BIT Consortium,Timothy R. Hughes,Ivan V. Kulakovskiy,Judith F. Kribelbauer-Swietek,Guido van Mierlo & Bart Deplancke
Nature Communications Published:05 August 2026
DOI:https://doi.org/10.1038/s41467-026-71387-y
Abstract
Transcription factors (TFs) are key players in eukaryotic gene regulation, but the DNA binding specificity of many TFs remains unknown. Here, we assay 284 mostly uncharacterized putative human TFs using selective microfluidics-based ligand enrichment followed by sequencing (SMiLE-seq), revealing 74 new DNA binding motifs. To investigate whether TFs lacking detectable motifs preferably bind epigenetically modified DNA, we develop methylation-sensitive SMiLE-seq (meSMiLE-seq), a microfluidic assay that simultaneously probes binding to methylated and unmethylated DNA. Using meSMiLE-seq, we assay 114 TFs and identify DNA-binding models for 48 proteins, including known methylation-sensitive binding modes for POU5F1 and RFX5. 11 TFs prefer methylated DNA or display alternative methylation-dependent motifs (e.g. PRDM13), while 13 show aversion to methylated sequences (e.g. USF3). Finally, we identify ZHX2 as a putative Z-DNA binder. Altogether, our study significantly expands the human TF codebook, while providing a versatile platform to quantitatively assay the impact of DNA modifications on TF binding.
