DNA-guided transcription factor cooperativity shapes face and limb mesenchyme

Seungsoo Kim; Ekaterina Morgunova; Sahin Naqvi; Seppe Goovaerts; Maram Bader; Mervenaz Koska; Alexander Popov; Christy Luong; Angela Pogson; Tomek Swigut; Peter Claes; Jussi Taipale; Joanna Wysocka

doi:10.1016/j.cell.2023.12.032

DNA-guided transcription factor cooperativity shapes face and limb mesenchyme

Cell. 2024 Feb 1;187(3):692-711.e26. doi: 10.1016/j.cell.2023.12.032. Epub 2024 Jan 22.

Authors

Seungsoo Kim¹, Ekaterina Morgunova², Sahin Naqvi³, Seppe Goovaerts⁴, Maram Bader⁵, Mervenaz Koska⁶, Alexander Popov⁷, Christy Luong⁸, Angela Pogson⁶, Tomek Swigut¹, Peter Claes⁹, Jussi Taipale¹⁰, Joanna Wysocka¹¹

Affiliations

¹ Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA.
² Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden.
³ Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
⁴ Medical Imaging Research Center, UZ Leuven, Leuven, Belgium; Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁵ Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
⁶ Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
⁷ European Synchrotron Radiation Facility, Grenoble, France.
⁸ Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
⁹ Medical Imaging Research Center, UZ Leuven, Leuven, Belgium; Department of Human Genetics, KU Leuven, Leuven, Belgium; Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium.
¹⁰ Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden; Department of Biochemistry, University of Cambridge, Cambridge, UK; Applied Tumor Genomics Program, University of Helsinki, Helsinki, Finland.
¹¹ Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA. Electronic address: wysocka@stanford.edu.

PMID: 38262408
PMCID: PMC10872279 (available on 2025-02-01)
DOI: 10.1016/j.cell.2023.12.032

Abstract

Transcription factors (TFs) can define distinct cellular identities despite nearly identical DNA-binding specificities. One mechanism for achieving regulatory specificity is DNA-guided TF cooperativity. Although in vitro studies suggest that it may be common, examples of such cooperativity remain scarce in cellular contexts. Here, we demonstrate how "Coordinator," a long DNA motif composed of common motifs bound by many basic helix-loop-helix (bHLH) and homeodomain (HD) TFs, uniquely defines the regulatory regions of embryonic face and limb mesenchyme. Coordinator guides cooperative and selective binding between the bHLH family mesenchymal regulator TWIST1 and a collective of HD factors associated with regional identities in the face and limb. TWIST1 is required for HD binding and open chromatin at Coordinator sites, whereas HD factors stabilize TWIST1 occupancy at Coordinator and titrate it away from HD-independent sites. This cooperativity results in the shared regulation of genes involved in cell-type and positional identities and ultimately shapes facial morphology and evolution.

Keywords: ALX factors; Coordinator; TWIST1; bHLH; cooperativity; face; homeodomain; limb; mesenchyme; neural crest; transcription factor.

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Binding Sites
DNA / metabolism
DNA-Binding Proteins* / metabolism
Embryonic Development*
Extremities / growth & development
Gene Expression Regulation
Humans
Mesoderm / metabolism
Mice
Transcription Factors* / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
DNA
DNA-Binding Proteins
Transcription Factors

Abstract

MeSH terms

Substances

Grants and funding