Role of LDB1 in the transition from chromatin looping to transcription activation

Abstract

Many questions remain about the relationship between chromatin loop formation and transcription. In erythroid cells, LDB1 is required for looping of the β-globin locus control region (LCR) to the active β-globin promoter. Dean and colleagues show that the LDB1 dimerization domain (DD) is necessary to restore LCR-promoter looping and transcription in LDB1-depleted cells. Deletion analysis reveals a conserved region of the LDB1 DD dispensable for dimerization and chromatin looping but necessary for transcription activation. The results thus uncouple enhancer–promoter looping from transcription at the β-globin locus.

Abstract

Many questions remain about how close association of genes and distant enhancers occurs and how this is linked to transcription activation. In erythroid cells, lim domain binding 1 (LDB1) protein is recruited to the β-globin locus via LMO2 and is required for looping of the β-globin locus control region (LCR) to the active β-globin promoter. We show that the LDB1 dimerization domain (DD) is necessary and, when fused to LMO2, sufficient to completely restore LCR–promoter looping and transcription in LDB1-depleted cells. The looping function of the DD is unique and irreplaceable by heterologous DDs. Dissection of the DD revealed distinct functional properties of conserved subdomains. Notably, a conserved helical region (DD4/5) is dispensable for LDB1 dimerization and chromatin looping but essential for transcriptional activation. DD4/5 is required for the recruitment of the coregulators FOG1 and the nucleosome remodeling and deacetylating (NuRD) complex. Lack of DD4/5 alters histone acetylation and RNA polymerase II recruitment and results in failure of the locus to migrate to the nuclear interior, as normally occurs during erythroid maturation. These results uncouple enhancer–promoter looping from nuclear migration and transcription activation and reveal new roles for LDB1 in these processes.