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(2023)", "@id": "/publications/97a0f850-b5a9-4994-b2eb-a24c706ae6b3/", "ID": "doi:10.1101/2023.07.19.549714", "date_published": "2023-07-19", "status": "current", "journal": "bioRxiv : the preprint server for biology", "abstract": "Mammalian embryogenesis commences with two pivotal and binary cell fate decisions  that give rise to three essential lineages, the trophectoderm (TE), the epiblast  (EPI) and the primitive endoderm (PrE). Although key signaling pathways and  transcription factors that control these early embryonic decisions have been  identified, the non-coding regulatory elements via which transcriptional  regulators enact these fates remain understudied. To address this gap, we have  characterized, at a genome-wide scale, enhancer activity and 3D connectivity in  embryo-derived stem cell lines that represent each of the early developmental  fates. We observed extensive enhancer remodeling and fine-scale 3D chromatin  rewiring among the three lineages, which strongly associate with transcriptional  changes, although there are distinct groups of genes that are irresponsive to  topological changes. In each lineage, a high degree of connectivity or \"hubness\"  positively correlates with levels of gene expression and enriches for cell-type  specific and essential genes. Genes within 3D hubs also show a significantly  stronger probability of coregulation across lineages, compared to genes in linear  proximity or within the same contact domains. By incorporating 3D chromatin  features, we build a novel predictive model for transcriptional regulation  (3D-HiChAT), which outperformed models that use only 1D promoter or proximal  variables in predicting levels and cell-type specificity of gene expression.  Using 3D-HiChAT, we performed genome-wide in silico perturbations to nominate  candidate functional enhancers and hubs in each cell lineage, and with CRISPRi  experiments we validated several novel enhancers that control expression of one  or more genes in their respective lineages. Our study comprehensively identifies  3D regulatory hubs associated with the earliest mammalian lineages and describes  their relationship to gene expression and cell identity, providing a framework to  understand lineage-specific transcriptional behaviors.", "title": "Systematic mapping and modeling of 3D enhancer-promoter interactions in early  mouse embryonic lineages reveal regulatory principles that determine the levels  and cell-type specificity of gene expression.", "display_title": "Murphy D et al. 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Although key signaling pathways and  transcription factors that control these early embryonic decisions have been  identified, the non-coding regulatory elements via which transcriptional  regulators enact these fates remain understudied. To address this gap, we have  characterized, at a genome-wide scale, enhancer activity and 3D connectivity in  embryo-derived stem cell lines that represent each of the early developmental  fates. We observed extensive enhancer remodeling and fine-scale 3D chromatin  rewiring among the three lineages, which strongly associate with transcriptional  changes, although there are distinct groups of genes that are irresponsive to  topological changes. In each lineage, a high degree of connectivity or \"hubness\"  positively correlates with levels of gene expression and enriches for cell-type  specific and essential genes. Genes within 3D hubs also show a significantly  stronger probability of coregulation across lineages, compared to genes in linear  proximity or within the same contact domains. By incorporating 3D chromatin  features, we build a novel predictive model for transcriptional regulation  (3D-HiChAT), which outperformed models that use only 1D promoter or proximal  variables in predicting levels and cell-type specificity of gene expression.  Using 3D-HiChAT, we performed genome-wide in silico perturbations to nominate  candidate functional enhancers and hubs in each cell lineage, and with CRISPRi  experiments we validated several novel enhancers that control expression of one  or more genes in their respective lineages. Our study comprehensively identifies  3D regulatory hubs associated with the earliest mammalian lineages and describes  their relationship to gene expression and cell identity, providing a framework to  understand lineage-specific transcriptional behaviors.", "date_published": "2023-07-19", "ID": "doi:10.1101/2023.07.19.549714", "@type": ["Publication", "Item"], "status": "current", "display_title": "Murphy D et al. 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