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.

Autor:	Murphy D; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States., Salataj E; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States., Di Giammartino DC; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States.; 3D Chromatin Conformation and RNA genomics laboratory, Instituto Italiano di Tecnologia (IIT), Center for Human Technologies (CHT), Genova, Italy (current affiliation)., Rodriguez-Hernaez J; Department of Pathology, New York University Langone Health, New York, NY 10016, USA.; Applied Bioinformatics Laboratory, New York University Langone Health, New York, NY 10016, USA., Kloetgen A; Department of Pathology, New York University Langone Health, New York, NY 10016, USA.; Applied Bioinformatics Laboratory, New York University Langone Health, New York, NY 10016, USA., Garg V; Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Biochemistry Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA., Char E; Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, 10065, New York, USA., Uyehara CM; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States., Ee LS; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States., Lee U; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States., Stadtfeld M; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States., Hadjantonakis AK; Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Biochemistry Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA., Tsirigos A; Department of Pathology, New York University Langone Health, New York, NY 10016, USA.; Applied Bioinformatics Laboratory, New York University Langone Health, New York, NY 10016, USA., Polyzos A; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States., Apostolou E; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jul 19. Date of Electronic Publication: 2023 Jul 19.
DOI:	10.1101/2023.07.19.549714
Abstrakt:	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. Competing Interests: Conflict of interest statement The authors declare that the above study was conducted in the absence of any commercial, financial, or personal relationships that could have appeared to influence the work reported in this article. All authors have approved the submitted version.
Databáze:	MEDLINE
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