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.
Highlights
Chromatin looping allows enhancer-bound regulatory factors to influence transcription
Chromatin looping enables the establishment of enhancer–promoter interactions, the role of transcription factors in shaping the three-dimensional organization of the genome during cell differentiation has been investigated in the context of only a few isolated loci[52,53,54]
We demonstrate that Pax[3] activity relies on the recruitment of the chromatin looping factor Ldb[1] (Fig. 3), which is required for establishing long-range interactions (Fig. 5) and, the proper execution of the myogenic program during embryonic development (Figs. 5 and 7)
Summary
Chromatin looping allows enhancer-bound regulatory factors to influence transcription. In the last decade, unbiased genome-wide analysis of chromosome conformation using Hi-C has identified that different parts of the genome with similar histone marks form two compartments characterized either by active transcription, being gene rich and having higher chromatin accessibility (type A), or being gene poor, displaying lower gene expression and repressive histone marks (type B)[2] These studies demonstrated the existence of topologically associated domains (referred as contact domains), which are chromosomal subunits displaying a higher contact frequency and defined by the binding of the Ctcf-Cohesin complex at the contact domain border[3,4,5].
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