Rapid redistribution and extensive binding of NANOG and GATA6 at shared regulatory elements underlie specification of divergent cell fates

Thompson, Joyce J.; Lee, Daniel J; Mitra, Apratim; Frail, Sarah; Dale, Ryan; Rocha, Pedro P.

doi:10.1101/2021.07.28.454132

Cited by 4 publications

(3 citation statements)

References 103 publications

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“…Hi-C and Capture-C library preparation and sequencing. HiC and Capture-C were performed and analyzed as described previously 62 . Embryonic tissue dissected and cells were dissociated as described above.…”

Section: Animalsmentioning

confidence: 99%

An epigenome atlas of neural progenitors within the embryonic mouse forebrain

Mitra

et al. 2021

Preprint

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While epigenetic modifications are critical for cell state changes throughout development, a detailed characterization of chromatin accessibility during neurogenesis has not been explored. We collected single-cell chromatin accessibility profiles from four distinct neurogenic regions of the embryonic mouse forebrain using single nuclei ATAC-Seq (snATAC-Seq). We identified thousands of differentially accessible peaks, many restricted to distinct progenitor cell types or brain regions. Integrating snATAC-Seq and transcriptome data, we characterized changes of chromatin accessibility at enhancers and promoters that were tightly coupled to transcript abundance during neurodevelopment. Integrating chromatin accessibility profiles from embryonic and adult interneurons with the iPSYCH2012 dataset revealed several disease-associated polymorphisms overlapped with accessible regions in embryonic cells. These findings highlight a diverse chromatin landscape in embryonic neural progenitors, extensive coordination between chromatin accessibility and gene expression during neuron fate determination, and open the door for future studies to define critical enhancer-promoter interactions that direct cell fate decisions.

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Section: Animalsmentioning

confidence: 99%

An epigenome atlas of neural progenitors within the embryonic mouse forebrain

Mitra

et al. 2021

Preprint

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“…Hi-C was performed as previously described ( 66 ). Briefly, isolated cells were fixed with formaldehyde.…”

Section: Methodsmentioning

confidence: 99%

Chromatin structure undergoes global and local reorganization during murine dendritic cell development and activation

Kurotaki

Kikuchi

Cui

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Classical dendritic cells (cDCs) are essential for immune responses and differentiate from hematopoietic stem cells via intermediate progenitors, such as monocyte−DC progenitors (MDPs) and common DC progenitors (CDPs). Upon infection, cDCs are activated and rapidly express host defense-related genes, such as those encoding cytokines and chemokines. Chromatin structures, including nuclear compartments and topologically associating domains (TADs), have been implicated in gene regulation. However, the extent and dynamics of their reorganization during cDC development and activation remain unknown. In this study, we comprehensively determined higher-order chromatin structures by Hi-C in DC progenitors and cDC subpopulations. During cDC differentiation, chromatin activation was initially induced at the MDP stage. Subsequently, a shift from inactive to active nuclear compartments occurred at the cDC gene loci in CDPs, which was followed by increased intra-TAD interactions and loop formation. Mechanistically, the transcription factor IRF8, indispensable for cDC differentiation, mediated chromatin activation and changes into the active compartments in DC progenitors, thereby possibly leading to cDC-specific gene induction. Using an infection model, we found that the chromatin structures of host defense-related gene loci were preestablished in unstimulated cDCs, indicating that the formation of higher-order chromatin structures prior to infection may contribute to the rapid responses to pathogens. Overall, these results suggest that chromatin structure reorganization is closely related to the establishment of cDC-specific gene expression and immune functions. This study advances the fundamental understanding of chromatin reorganization in cDC differentiation and activation.

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“…Among them, mouse ESCs that represent the naive EPI state have been extensively characterized by us and others using multiple -omics assays and functional screens 26,27,60,61 . However, only a few recent studies have started to shed light on the enhancer landscape and 3D chromatin organization of TSC and less so of XEN cells [62][63][64][65][66][67][68][69] whilst direct comparisons of the 3 lineages are missing.…”

Section: Introductionmentioning

confidence: 99%

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

Murphy,

Salataj,

Di Giammartino

et al. 2023

Preprint

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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.

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Rapid redistribution and extensive binding of NANOG and GATA6 at shared regulatory elements underlie specification of divergent cell fates

Cited by 4 publications

References 103 publications

An epigenome atlas of neural progenitors within the embryonic mouse forebrain

An epigenome atlas of neural progenitors within the embryonic mouse forebrain

Chromatin structure undergoes global and local reorganization during murine dendritic cell development and activation

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

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