Ensembles of genome-coverage single-cell histone modifications reveal epigenetic lineages during mouse preimplantation development
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PROVIDER: PRJNA984604 | ENA |
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Project description:Ensembles of genome-coverage single-cell histone modifications reveal epigenetic lineages during mouse preimplantation development II
| PRJNA1081401 | ENA
Project description:We applied TACIT to profile seven histone modifications at single-cell resolution in mouse early embryos from zygotes to blastocysts. Profound epigenetic resetting during early embryo development from fertilization to blastocyst ensures zygotic genome activation and also begets progressive cellular heterogeneities1-6. Mapping single-cell epigenomic profiles of core histone modifications covering each individual cell onto the lineage tree (epigenetic lineages) is a fundamental goal in developmental biology. Here, we develop a method, TACIT, achieving genome-coverage single-cell profiling of seven histone modifications in mouse early embryos from zygotes to blastocysts. TACIT yields up to half million fragments per cell with peaks equivalent of bulk assays. Integrating these single-cell histone modifications with scRNA-seq data7, we chart a cell-kinship informed epigenetic lineage landscape. Multimodal chromatin state annotations show that the ZGA onset at early 2-cell stage already primes heterogeneities in totipotency. Epigenetic lineages also allow for nominating totipotency gene regulatory networks including stage-specific transposable elements and putative transcription factors (TFs). In addition, machine learning models together with single-cell co-profiles of multiple histone modifications facilitate prediction of the earliest cell branching toward inner cell mass (ICM) and trophectoderm (TE) in latent multimodal space as well as feature regulatory elements and previously unknown lineage-specifying TFs. Together, our work reconstructs single-cell holistic epigenetic lineages, elucidating multimodal regulation of cellular heterogeneities and cell fate priming during mouse pre-implantation development.
2024-12-21 | GSE235109 | GEO
Project description:Profound epigenetic resetting during early embryo development from fertilization to blastocyst ensures zygotic genome activation and also begets progressive cellular heterogeneities1-6. Mapping single-cell epigenomic profiles of core histone modifications covering each individual cell onto the lineage tree (epigenetic lineages) is a fundamental goal in developmental biology. Here, we develop a method, TACIT, achieving genome-coverage single-cell profiling of seven histone modifications in mouse early embryos from zygotes to blastocysts. TACIT yields up to half million fragments per cell with peaks equivalent of bulk assays. Integrating these single-cell histone modifications with scRNA-seq data7, we chart a cell-kinship informed epigenetic lineage landscape. Multimodal chromatin state annotations show that the ZGA onset at early 2-cell stage already primes heterogeneities in totipotency. Epigenetic lineages also allow for nominating totipotency gene regulatory networks including stage-specific transposable elements and putative transcription factors (TFs). In addition, machine learning models together with single-cell co-profiles of multiple histone modifications facilitate prediction of the earliest cell branching toward inner cell mass (ICM) and trophectoderm (TE) in latent multimodal space as well as feature regulatory elements and previously unknown lineage-specifying TFs. Together, our work reconstructs single-cell holistic epigenetic lineages, elucidating multimodal regulation of cellular heterogeneities and cell fate priming during mouse pre-implantation development.
2024-12-21 | GSE259393 | GEO
Project description:The physical manifestations of memory formation and recall are fundamental questions that remain unresolved. At the cellular level, ensembles of neurons called engrams are activated by learning events and control memory recall. Astrocytes are in close proximity to neurons and engage in a range of activities that support neurotransmission and circuit plasticity. Moreover, astrocytes exhibit experience dependent plasticity; however whether specific ensembles of astrocytes participate in memory recall remains obscure. Here we show that learning events induce c-Fos expression in a subset of hippocampal astrocytes, which subsequently regulates hippocampal circuit function. Intersectional, c-Fos based labeling of these astrocyte ensembles after learning events reveals that they are closely affiliated with engram neurons, while re-activation of these astrocyte ensembles stimulates memory recall. At the molecular level, these astrocyte ensembles exhibit elevated expression of NFIA and its selective deletion from this population suppresses memory recall. Together, our studies identify learning-associated astrocyte ensembles as a new form of plasticity that is sufficient to provoke memory recall, while implicating astrocytes as a reservoir for the storage of memories.
2024-06-30 | GSE254016 | GEO
Project description:Maladaptive reward seeking is a hallmark of cocaine use disorder. To develop therapeutic targets, it is critical to understand the neurobiological changes specific to cocaine-seeking without altering the seeking of natural rewards, e.g., sucrose. The prefrontal cortex (PFC) and the nucleus accumbens core (NAcore) are known regions associated with cocaine- and sucrose-seeking ensembles, i.e., a sparse population of co-activated neurons. Within ensembles, transcriptomic alterations in the PFC and NAcore underlie the learning and persistence of cocaine- and sucrose-seeking behavior. However, transcriptomes exclusively driving cocaine seeking independent from sucrose seeking have not yet been defined using a within-subject approach. Using Ai14:cFos-TRAP2 transgenic mice in a dual cocaine and sucrose self-administration model, we fluorescently sorted (FACS) and characterized (RNAseq) the transcriptomes defining cocaine- and sucrose-seeking ensembles. We found reward- and region-specific transcriptomic changes that will help develop clinically relevant genetic approaches to decrease cocaine-seeking behavior without altering non-drug reward-based positive reinforcement.
2023-11-08 | GSE247029 | GEO
Project description:Preimplantation stages of mouse embryo development involve temporal and spatial specification and segregation of three late blastocyst cell lineages; trophectoderm (TE), primitive endoderm (PrE) and epiblast (EPI). Spatial separation of the outer TE lineage from the two inner-cell-mass (ICM) lineages (PrE and EPI) starts with the 8- to 16-cell transition and concludes following transit through the 16- to 32-cell stages. This results in a nascent early blastocyst ICM derived from descendants of primary founding inner cells and a secondarily contributed population; of which subsequent relative EPI versus PrE potencies are subject to debate. We showed that generation of primary but not the secondary ICM populations is highly dependent on temporally discreet activation of the mammalian target of rapamycin (mTOR – specifically mTORC1) around 8-cell stage M-phase entry. Moreover, that this role is mediated via the regulated function of the 7-methylguanosine- (7mG) cap binding initiation complex (EIF4F) and potentiating the translation of a subset of key but otherwise intransigent mRNAs containing 5’ UTR terminal oligopyrimidine (TOP-) sequence motifs. To find out translation of which mRNAs is regulated by mTOR during 8- to 16-cell transition, we analysed proteomes of control and mTOR-inhibited embryos during this time window.
2023-08-18 | PXD039423 | Pride
Project description:Mouse preimplantation imprinting
| PRJNA638349 | ENA
Project description:Nuclear receptors function as ligand-regulated transcription factors whose ability to regulate diverse physiological processes is closely linked with conformational changes induced upon ligand binding. Understanding how conformational populations of nuclear receptors are shifted by various ligands could illuminate strategies for the design of synthetic modulators to regulate specific transcriptional programs. Here, we investigate ligand-induced conformational changes using a reconstructed, ancestral nuclear receptor. By making substitutions at a key position, we engineer receptor variants with altered ligand specificities. We use atomistic molecular dynamics (MD) simulations with enhanced sampling to generate ensembles of wildtype and engineered receptors in combination with multiple ligands, followed by conformational analysis and prediction of ligand activity. We combine cellular and biophysical experiments to allow correlation of MD-based predictions with functional ligand profiles, as well as elucidation of mechanisms underlying altered transcription in receptor variants. We determine that conformational ensembles accurately predict ligand responses based on observed population shifts, even within engineered receptors that were constitutively active or transcriptionally unresponsive in experiments. These studies provide a platform which will allow structural characterization of physiologically-relevant conformational ensembles, as well as provide the ability to design and predict transcriptional responses in novel ligands.
2022-10-12 | PXD036076 | Pride
Project description:Genome-scale deconvolution of RNA structure ensembles
| PRJNA663861 | ENA
Project description:Learning-Associated Astrocyte Ensembles Regulate Memory Recall
| PRJNA1068117 | ENA