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Global rewiring of cis-regulatory units upon lineage commitment of human embryonic stem cells

ABSTRACT: Lineage commitment is characterised by orchestrated changes in gene expression and chromatin state. Long-range elements such as enhancers coordinate lineage-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. However, the target genes of most long-range elements remain unknown, hindering an integrated understanding of cis-regulatory gene control. Here, we generate a high-resolution atlas of chromosomal interactions involving ~22,000 gene promoters in human pluripotent and lineage-committed cells, identifying putative target genes for known and predicted enhancer elements. We jointly consider promoters and their associated interacting regions as “cis-regulatory units” that potentially integrate and stabilise regulatory inputs from individual elements. We reveal extensive dynamics of cis-regulatory units upon lineage commitment, including the acquisition and loss of promoter interactions, as well as chromatin state changes at preformed interactions. Finally, we show that reconfiguration of cis-regulatory units associates with changes in target gene expression. Our results therefore provide a high-resolution view of promoter interactome dynamics during lineage commitment and provide insights into the mechanisms of developmental transcriptional regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86821 | GEO | 2017/03/23

SECONDARY ACCESSION(S): PRJNA342627

REPOSITORIES: GEO

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Homo sapiens

Project description:Global rewiring of cis-regulatory units upon lineage commitment of human embryonic stem cells

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Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation

Project description:Lineage commitment and differentiation is driven by the concerted action of master transcriptional regulators at their target chromatin sites. Multiple efforts have characterized the key transcription factors (TFs) that determine the various hematopoietic lineages. However, the temporal interactions between individual TFs and their chromatin targets during differentiation and how these interactions dictate lineage commitment remains poorly understood. We performed dense, daily, temporal profiling of chromatin accessibility (DNase I-seq) and gene expression changes (total RNA-seq) along ex vivo human erythropoiesis to comprehensively define developmentally regulated DNase I hypersensitive sites (DHSs) and transcripts. We link both distal DHSs to their target gene promoters and individual TFs to their target DHSs, revealing that the regulatory landscape is organized in distinct sequential regulatory modules that regulate lineage restriction and maturation. Finally, direct comparison of transcriptional dynamics (bulk and single-cell) and lineage potential between erythropoiesis and megakaryopoiesis uncovers differential fate commitment dynamics between the two lineages as they exit the stem and progenitor stage. Collectively, these data provide novel insights into the global regulatory landscape during hematopoiesis.

2021-09-30 | GSE182816 | GEO

Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation [DNaseI-seq]

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Comprehensive, high resolution analysis of cis-acting regulatory networks at the alpha globin locus (HTS)

Project description:We have combined the 4C chromosome conformation capture protocol with high throughput, genome-wide sequence analysis to characterise in full a cis-acting regulatory network at a single locus. In contrast to methods which identify large interacting regions (10-1000kb), the 4C approach provides a comprehensive, high resolution analysis of a specific locus with the aim of defining, in detail, all cis- regulatory elements controlling a single gene or gene cluster. Using the human M-NM-1-globin locus as a model we detected all known local and long-range interactions with this gene cluster. In addition we identified two interactions with genes located 300 kb (NME4) and 625 kb (FAM173a) from the M-NM-1-globin cluster. Using paired-end sequencing it was possible for the first time to identify interactions between specific subsets of cis-regulatory elements in populations of cells and within individual cells. Two biological replicates of 4C amplification from the promoters of the human HBA gene promoters. Sequenced as paired end fragments usinig Illumina GAII

2013-06-06 | E-GEOD-42382 | biostudies-arrayexpress

Lineage-specific genome architecture links disease variants to target genes

Project description:Long-range interactions between DNA regulatory elements and their target genes play major roles in gene regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary haematopoietic cell types. We show that long-range promoter interactions are highly cell-type specific, preferentially linking active promoters and enhancers. Patterns of promoter interactions reflect cell lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched for expression quantitative trait loci with effects on their interacting target genes. We exploit this rich resource of interactome maps to connect non-coding disease variants to their target promoters, identifying thousands of new disease-candidate genes, and implicating a number of gene pathways in disease susceptibility. Our results demonstrate the power of promoter interactomes from primary cells to reveal insights into genomic regulatory mechanisms underlying common diseases.

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Genomewide analysis of Insulator protein binding sites in Drosophila embryos at E0-12

Project description:Insulators are DNA sequences that control the interactions among genomic regulatory elements and act as chromatin boundaries. A thorough understanding of their location and function is necessary to address the complexities of metazoan gene regulation. We studied by ChIP-chip the genome-wide binding sites of 6 insulator-associated proteins – dCTCF, CP190, BEAF-32, Su(Hw), Mod(mdg4) and GAF – to obtain the first comprehensive map of insulator elements in Drosophila embryos. We identify over 14,000 putative insulators, including all previously known insulators. We find two major classes of insulators defined by dCTCF/CP190/BEAF-32 and Su(Hw) respectively. Distributional analyses of insulators revealed that particular sub-classes of insulator elements are excluded between cis-regulatory elements and their target promoters, divide differentially expressed, alternative, and divergent promoters, act as chromatin boundaries, are associated with chromosomal breakpoints among species, and are embedded within active chromatin domains. Together, these results provide a map demarcating the boundaries of gene regulatory units, and a framework for understanding insulator function during the development and evolution of Drosophila. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf

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Project description:We have combined the 4C chromosome conformation capture protocol with high throughput, genome-wide sequence analysis to characterise in full a cis-acting regulatory network at a single locus. In contrast to methods which identify large interacting regions (10-1000kb), the 4C approach provides a comprehensive, high resolution analysis of a specific locus with the aim of defining, in detail, all cis- regulatory elements controlling a single gene or gene cluster. Using the human M-NM-1-globin locus as a model we detected all known local and long-range interactions with this gene cluster. In addition we identified two interactions with genes located 300 kb (NME4) and 625 kb (FAM173a) from the M-NM-1-globin cluster. Using paired-end sequencing it was possible for the first time to identify interactions between specific subsets of cis-regulatory elements in populations of cells and within individual cells. Two biological replicates of 4C amplification from the promoters of the human HBA and HBB genes and B-Cell controls. Quality of B-cell material was confirmed using amplification from a CTCF bound region associated with Human Axin Gene.

2013-06-06 | E-GEOD-42383 | biostudies-arrayexpress

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