Pax3 cooperates with Ldb1 to direct local chromosome architecture during myogenic lineage specification

Alessandro Magli (), June Baik, Pruthvi Pota, Carolina Ortiz Cordero, Il-Youp Kwak, Daniel J. Garry, Paul E. Love, Brian D. Dynlacht and Rita C. R. Perlingeiro ()
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Alessandro Magli: Lillehei Heart Institute, University of Minnesota
June Baik: Lillehei Heart Institute, University of Minnesota
Pruthvi Pota: Lillehei Heart Institute, University of Minnesota
Carolina Ortiz Cordero: Lillehei Heart Institute, University of Minnesota
Il-Youp Kwak: Lillehei Heart Institute, University of Minnesota
Daniel J. Garry: Lillehei Heart Institute, University of Minnesota
Paul E. Love: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Brian D. Dynlacht: New York University Cancer Institute, New York University School of Medicine
Rita C. R. Perlingeiro: Lillehei Heart Institute, University of Minnesota

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Chromatin looping allows enhancer-bound regulatory factors to influence transcription. Large domains, referred to as topologically associated domains, participate in genome organization. However, the mechanisms underlining interactions within these domains, which control gene expression, are not fully understood. Here we report that activation of embryonic myogenesis is associated with establishment of long-range chromatin interactions centered on Pax3-bound loci. Using mass spectrometry and genomic studies, we identify the ubiquitously expressed LIM-domain binding protein 1 (Ldb1) as the mediator of looping interactions at a subset of Pax3 binding sites. Ldb1 is recruited to Pax3-bound elements independently of CTCF-Cohesin, and is necessary for efficient deposition of H3K4me1 at these sites and chromatin looping. When Ldb1 is deleted in Pax3-expressing cells in vivo, specification of migratory myogenic progenitors is severely impaired. These results highlight Ldb1 requirement for Pax3 myogenic activity and demonstrate how transcription factors can promote formation of sub-topologically associated domain interactions involved in lineage specification.

Date: 2019
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DOI: 10.1038/s41467-019-10318-6

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