Construction of an atlas of transcription factor binding during mouse development identifies popular regulatory...

Gene regulators physically associate with the genome, in a combinatorial fashion, to drive tissue-specific gene expression. Uncovering the genome-wide activity of all gene regulators across tissues is therefore needed to understand gene regulation during development. Here, we take a first step towards this goal. Using CUT&RUN, we systematically mapped genome-wide binding profiles of key transcription factors and co-factors that mediate ontogenetically relevant signaling pathways in select mouse tissues at two developmental stages. Computation of the datasets unveiled tissue- and time-specific activity for each gene regulator. We identified 'popular' regulatory regions that are bound by a multitude of regulators, which tend to be more evolutionarily conserved. Consistently, they lie near the transcription start site of genes for which dysregulation results in early embryonic lethality. Moreover, the human homologs of these regions are similarly bound by many gene regulators and are highly conserved, indicating a retained relevance for human development. This work constitutes a decisive step towards understanding how the genome is simultaneously read and used by gene regulators in a holistic fashion to drive embryonic development.