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SIS-seq, a molecular ‘time machine’, connects single cell fate with gene programs

ABSTRACT: Conventional single cell RNA-seq methods are destructive, such that a given cell cannot also then be tested for fate and function, without a time machine. Here, we develop a clonal method SIS-seq, whereby single cells are allowed to divide, and progeny cells are assayed separately in SISter conditions; some for fate, others by RNA-seq. By cross-correlating fate and gene expression within a clone, and doing this for many clones, we can identify the earliest gene expression signatures of dendritic cell subset development. SIS-seq could be used to study other populations harboring clonal heterogeneity, including stem, reprogrammed and cancer cells to reveal the transcriptional origins of fate decisions.

ORGANISM(S): Mus musculus

PROVIDER: GSE119097 | GEO | 2018/08/28

REPOSITORIES: GEO

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Clonal multi-omics in DC development

Project description:Despite major developments in single cell multi-omics approaches, a single stem or progenitor cell can only be tested once. Here we develop ‘clonal multi-omics’, where recent daughters of a clone act as surrogates of the parental cell allowing multiple tests of its molecular profile and/or cellular fate under different conditions. We first present SIS-seq – a novel clonal method whereby siblings are examined in parallel for gene expression by RNA-seq, or for fate after culture. We use this method to identify, then validate using CRISPR, the genes expressed in single haematopoietic progenitors that control the development of the different dendritic cell (DC) subtypes. In this way, Bcor is identified as a suppressor of plasmacytoid DC (pDC) and conventional DC subtype 2 (cDC2) numbers during Flt3 ligand-mediated ‘emergency’ DC development. Using a complementary method SIS-skew – where WT and BcorKO siblings of the same clone are examined in parallel for fate – we discover that Bcor restricts clonal expansion, especially for generation of cDC2s, and suppresses clonal fate potential, especially for pDCs. SIS-seq and SIS-skew therefore represent novel and broadly applicable clonal multiomics approaches that can reveal the molecular and cellular mechanisms governing cell function at a single cell level, including after genetic or extrinsic factor perturbation. This SuperSeries is composed of the SubSeries listed below.

2020-07-01 | GSE153676 | GEO

Clonal multi-omics reveals Bcor as a regulator of dendritic cell development and its action at a clonal level

Project description:Despite major developments in single cell multi-omics approaches, a single stem or progenitor cell can only be tested once. Here we develop ‘clonal multi-omics’, where recent daughters of a clone act as surrogates of the parental cell allowing multiple tests of its molecular profile and/or cellular fate under different conditions. We first present SIS-seq – a novel clonal method whereby siblings are examined in parallel for gene expression by RNA-seq, or for fate after culture. We use this method to identify, then validate using CRISPR, the genes expressed in single haematopoietic progenitors that control the development of the different dendritic cell (DC) subtypes. In this way, Bcor is identified as a suppressor of plasmacytoid DC (pDC) and conventional DC subtype 2 (cDC2) numbers during Flt3 ligand-mediated ‘emergency’ DC development. Using a complementary method SIS-skew – where WT and BcorKO siblings of the same clone are examined in parallel for fate – we discover that Bcor restricts clonal expansion, especially for generation of cDC2s, and suppresses clonal fate potential, especially for pDCs. SIS-seq and SIS-skew therefore represent novel and broadly applicable clonal multi-omics approaches that could reveal the molecular and cellular mechanisms governing stem, immune, reprogrammed and cancer cell function at a single cell level, including after genetic or extrinsic factor perturbation.

2020-07-01 | GSE153675 | GEO

SIS-seq, a molecular ‘time machine’, connects single cell fate with gene programs

Project description:SIS-seq, a molecular ‘time machine’, connects single cell fate with gene programs

| PRJNA488094 | ENA

Notch signaling between cerebellar granule cell progenitors

Project description:During cerebellar development, maternal granule cell progenitors (GCPs) divide to produce not only postmitotic granule cells (GCs) but also sister GCPs. However, molecular machinery to proportionally produce distinct sister cell types from seemingly uniform GCPs is still elusive. Here we report Notch signaling makes a difference among GCPs, leading to their proportional differentiation.

2020-06-27 | GSE153313 | GEO

Collier1996 - Delta Notch intercellular signalling and lateral inhibition

Project description:ODE model describing how slight variations in Notch and Delta cellular concentrations, through lateral inhibition, lead to cells with different states of differentiation. Lateral inhibition is a process whereby a given cell adopting a given fate prevents its immediate neighbouring cells from doing likewise. Notch and Delta are interacting transmembrane proteins and according to this model, lateral inhibition is due to a process where the inhibited cells (where notch has been activated by Delta) loose their ability to inhibit other cells (by synthesizing Delta). This process creates a feedback loop where cells with more delta proteins on their surface inhibit their immediate neighbours and adopt a different cell fate than those neighbours.

2022-04-05 | BIOMD0000001047 | BioModels

Cell fate inclination within 2-cell and 4-cell mouse embryos revealed by single-cell RNA sequencing

Project description:It remains an open question when and how the first cell fate decision is made in mammals. Using deep single-cell RNA-seq of matched sister blastomeres, we report highly reproducible interblastomere differences among ten 2-cell and five 4-cell mouse embryos. Inter-blastomere gene expression differences dominated between-embryo differences and noises, and were sufficient to cluster sister blastomeres into distinct groups. Dozens of protein-coding genes exhibited reproducible bimodal expression in sister blastomeres (0 vs. 1e3-1e6 of FPKM), which cannot be explained by random fluctuations. The protein expression of one of these bimodal genes, Gadd45a, exhibited clear inter-blastomeric contrasts. We traced some of the bimodal mRNA expressions to embryonic genome activation, and others to blastomere-specific RNA depletion. Inter-blastomere differences created co-expression gene networks that were much stronger and larger than those that can be possibly created by random noises. The highly correlated gene pairs at the 4-cell overlapped with those showing the same directions of differential expression between inner cell mass (ICM) and trophectoderm (TE). These data substantiate the hypothesis of inter-blastomere differences in 2- and 4-cell mouse embryos, and associate these differences with ICM/TE differences. 9 zygotes, 10 2-cell, and 5 4-cell mouse (C57BL/6) embryos were collected and multi-cell embryos were separated into blastomeres. 4 inner cell mass (ICM) and 3 trophectoderm (TE) samples are also extracted from mouse blastocysts. Transcriptome profiles for all samples are obtained via Smart-seq protocol.

2014-07-29 | E-GEOD-57249 | biostudies-arrayexpress

Mus musculus

Project description:Clonal analysis of lineage fate in unperturbed hematopoiesis

| PRJNA355645 | ENA

Study Nocte's functions in transcription and translation in Drosophila eye discs

Project description:Nocte is an RNA binding protein but its functions in Drosophila eye development is unknown. We found that knockdown of nocte by RNAi in Drosophila eyes leads to small and rough eye phenotypes. We detected nocte's functions at mRNA levels by doing RNA-seq with purified polyA mRNA. We detected nocte's functions in mRNA translation by doing Ribo-seq and total RNA-seq to calculate the translation efficiencies.

2023-11-10 | GSE232395 | GEO

Promotion of Subtotal Uterine Reconstruction by a Tissue-engineered Uterus Biomimeticing Structure and Extracellular Matrix Microenvironment

Project description:To better characterize the ECM signature of the ECMEC-SIS and ECMSMC-PU/SIS, a 4D label free proteomic analyses was carried out. In total 2761 and 1520 proteins have been identified for the ECMEC-SIS and ECMSMC-PU/SIS, respectively, including 1055 in common . An ECM-specific categorization database, MatrisomeDB 2.0, was employed to analyze the ECM matrisome protein and ECM-associated proteins.In the ECMEC-SIS group, the ECM matisome, matrisome-associated, and other proteins have accounted for 17.87%, 17.00%, and 65.13%, respectively. However, the proportion of ECM proteins, especially glycoproteins and regulators, was greater in ECMSMC-PU/SIS group compared with the ECMEC-SIS group. In the ECMSMC-PU/SIS group, the ECM matisome, matrisome-associated, and other proteins have accounted for 26.39%, 20.85%, and 52.77%, respectively.

2024-01-26 | PXD041467 | Pride

Project description:Clonal heterogeneity influences the fate of new adaptive mutations

| PRJEB13491 | ENA

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