Abstract
We investigate the three-dimensional (3D) conformations of the α-globin locus at the single-allele level in murine embryonic stem cells (ESCs) and erythroid cells, combining polymer physics models and high-resolution Capture-C data. Model predictions are validated against independent fluorescence insitu hybridization (FISH) data measuring pairwise distances, and Tri-C data identifying three-way contacts. The architecture is rearranged during the transition from ESCs to erythroid cells, associated with the activation of the globin genes. We find that in ESCs, the spatial organization conforms to a highly intermingled 3D structure involving non-specific contacts, whereas in erythroid cells the α-globin genes and their enhancers form a self-contained domain, arranged in a folded hairpin conformation, separated from intermingling flanking regions by a thermodynamic mechanism of micro-phase separation. The flanking regions are rich in convergent CTCF sites, which only marginally participate in the erythroid-specific gene-enhancer contacts, suggesting that beyond the interaction of CTCF sites, multiple molecular mechanisms cooperate to form an interacting domain.
Highlights
During development, gene activity is controlled by cis-regulatory elements, such as promoters and distal enhancers, that physically contact their target genes in a dynamic architecture (Dekker and Mirny, 2016; Spielmann et al, 2018)
We studied the a- and b-globin loci in mouse embryonic stem cells (ESCs) and in primary erythroid cells, where the globin genes are respectively silent and active
In ESCs the locus is organized into a large uniform domain, where no preferential contact forms between its regulatory elements, whereas in erythroid cells sharper interaction domains form, one of which contains the globin genes and their enhancers
Summary
Gene activity is controlled by cis-regulatory elements, such as promoters and distal enhancers, that physically contact their target genes in a dynamic architecture (Dekker and Mirny, 2016; Spielmann et al, 2018). Genomic contacts play a key role in regulating transcription by modulating the associations between genes and regulators. Disruption of such interactions may be associated with abnormal gene expression and development (Franke et al, 2016; Lupian ̃ ez et al, 2015; Valton and Dekker, 2016). We used chromatin models from polymer physics (Barbieri et al, 2012; Bianco et al, 2018; Chiariello et al, 2016), informed with recent high-resolution Capture-C data (Oudelaar et al, 2018), to obtain spatial information at the level of single alleles
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