Ph.D., Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN - Stem Cell Institute, University of Minnesota, Minneapolis, MN
2.00 - Aula B102
Via Sommarive, 9 - Povo, Trento
Chromatin topology is essential in gene regulation as it establishes the framework for nuclear chromosome organization and, ultimately, the interactions between distal regulatory elements and gene promoters. The observations that 1) Topologically Associated Domains (TADs) are highly conserved among multiple cell types and 2) genome compartmentalization is maintained upon TADs disruption, suggest that chromatin remodeling and enhancer-promoter interactions at a sub-TAD scale may represent the main drivers responsible for the activation of specific gene expression programs. Despite the existence of loci where looping interactions control gene expression (e.g. LCR:β-globin, and the Bithorax locus), the extent to which lineage-specific transcription factors (TF) shape the three-dimensional organization of the genome during differentiation is still not clearly understood. Here we use the skeletal myogenic lineage as a model to study tissue-specific gene expression induced by the transcription factor Pax3. Our genome-wide analyses reveal that activation of the embryonic myogenic program is associated with the time-dependent establishment of long-range chromatin interactions centered on Pax3-bound loci. Using mass spectrometry and genomic studies, we next identify the ubiquitously expressed LIM-domain binding protein 1 (Ldb1) as the mediator of looping interactions at a subset of Pax3 binding sites. Through loss- and gain-of-function studies, we demonstrate that Ldb1 recruitment at Pax3-bound loci is necessary for both epigenetic remodeling and establishment of the chromatin architecture landscape. Importantly, when Ldb1 is deleted in Pax3-expressing cells in vivo, specification of migratory myogenic progenitors is severely impaired. Altogether, these results illuminate the role of looping, facilitated by transcription factor-mediated recruitment of Ldb1, in the activation of lineage-specific gene expression.