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Systematic mapping of TF-mediated cell fate changes by a pooled induction coupled with scRNA-seq and multi-omics approaches

ABSTRACT: Transcriptional regulation controls various cellular functions via the interactions between cell-type-specific transcription factors (TFs) and their chromosomal targets. While multiple TFs capable of converting cell fates from one to another have been reported, only a few systematic studies aiming to understand the fate conversion potential of numerous individual TFs have been reported. Here, we propose an iTF-seq method (pooled induction of individual TFs followed by single-cell RNA sequencing) to identify potent TFs capable of converting cell fates and elucidate their lineage specification potential at a single-cell level. Enabling metabolic biotinylation of TFs during the process, the method allows subsequent multi-omics approaches to understand underlying action mechanisms of TFs during cell fate changes. Our pilot iTF-seq of 80 TFs in mouse embryonic stem (ES) cells has identified multiple previously known and unknown TFs triggering transcriptome changes within one day of TF induction. Subsequent tests revealed that Gcm1 and Otx2 function as activators and pioneer factors, while they resulted in distinct cell fates and gene expression programs upon induction.

ORGANISM(S): Mus musculus

PROVIDER: GSE218628 | GEO | 2024/02/05

REPOSITORIES: GEO

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Systematic mapping of TF-mediated cell fate changes by a pooled inductioncoupled with scRNA-seq and multi-omics approaches

Project description:Transcriptional regulation controls various cellular functions via the interactionsbetween cell-type-specific transcription factors (TFs) and their chromosomaltargets. While multiple TFs capable of converting cell fates from one to anotherhave been reported, only a few systematic studies aiming to understand thefate conversion potential of numerous individual TFs have been reported. Here,we propose an iTF-seq method (pooled induction of individual TFs followed bysingle-cell RNA sequencing) to identify potent TFs capable of converting cellfates and elucidate their lineage specification potential at a single-cell level.Enabling metabolic biotinylation of TFs during the process, the method allowssubsequent multi-omics approaches to understand underlying actionmechanisms of TFs during cell fate changes. Our pilot iTF-seq of 80 TFs inmouse embryonic stem (ES) cells has identified multiple previously known andunknown TFs triggering transcriptome changes within one day of TF induction.Subsequent tests revealed that Gcm1 and Otx2 function as activators andpioneer factors, while they resulted in distinct cell fates and gene expressionprograms upon induction.

2024-02-05 | GSE220724 | GEO

A Single Cell Transcriptomic Analysis of Human Neocortical Development

Project description:<p>Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We produced single cell transcriptomic profiles for 40,000 cells at mid-gestation to define deep expression profiles corresponding to all known major cell types at this developmental period and compare this with bulk tissue profiles. We identified multiple transcription factors (TFs) and co-factors expressed in specific cell types, including multiple new cell-type-specific relationships, providing an unprecedented resource for understanding human neocortical development and evolution. This includes the first single-cell characterization of human subplate neurons and subtypes of developing glutamatergic and GABAergic neurons. We also used these data to deconvolute single cell regulatory networks that connect regulatory elements and transcriptional drivers to single cell gene expression programs in the developing CNS. We characterized major developmental trajectories that tie cell cycle progression with early cell fate decisions during early neurogenesis. Remarkably, we found that differentiation occurs on a transcriptomic continuum, so that differentiating cells not only express the few key TFs that drive cell fates, but express broad, mixed cell-type transcriptomes prior to telophase. Finally, we mapped neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types in ASD, ID, and epilepsy, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.</p>

| phs001836 | dbGaP

Controlled induction of 49 transcription factors in transgenic mouse ES cell lines

Project description:Controlled induction of individual transcription factors (TFs) in embryonic stem cells (ESCs) with subsequent global gene expression profiling is a promising approach for identification of downstream genes regulated by these TFs in a relatively promiscuous epigenetic background. Here we generated and characterized mouse ESCs clones with 49 doxycycline-controllable TFs as a continuation of the NIA Mouse ESC Bank project. Together with the previous clone libraries, the project now comprises 186 TFs (ca. 10% of all TFs in the genome). Induction of individual TFs shifts the transcriptome towards specific differentiation fates (e.g., neural for Myt1, St18; fibroblasts and osteoblasts for Pitx1, Pitx2, Barhl2, and Lmx1a; thymocytes for Myb; lymph nodes and spleen for Etv2 and Plac1, and ovary for Pitx1, Pitx2, and Dmrtc2). Gene set enrichment analysis for expression profile change after induction of TFs provides additional information on the functions and phenotypes associated with these TFs. These data could facilitate methods for generating various types of cells in regenerative medicine as well as ameliorating pathogenic phenotypes in gene therapy. Dox- overexpressing transcription factor vs. Dox+ (control).

2016-07-21 | E-GEOD-72350 | biostudies-arrayexpress

Chemical reprogramming of mouse embryonic and adult fibroblast into endoderm lineage

Project description:We report here an approach to redirect somatic cell fate under chemically defined conditions without transcription factors. We start by converting mouse embryonic fibroblasts (MEFs) to epithelial-like cells (ciELC) with chemicals and growth factors. Subsequent cell fate mapping reveals a robust induction of SOX17 in the resulting ELCs that can be further reprogrammed to endodermal progenitor cells (ciEPC). Interestingly, these cells can self-renew in vitro and further differentiate into albumin-producing hepatocytes that can rescue mice from acute live injury. Our results demonstrate a rational approach to convert MEFs to hepatocytes and suggest that this mechanism-driven approach may be generalized for other cells.

2017-10-04 | GSE104555 | GEO

Controlled induction of 49 transcription factors in transgenic mouse ES cell lines

2016-07-21 | GSE72350 | GEO

Shewanella sp. ANA-3

Project description:Bacterium capable of converting arsenate to arsenite

| PRJNA13905 | ENA

Transcription factors interfering with dedifferentiation induce direct conversion

Project description:Although transcription factor(TF)s regulate differentiation-related processes, including dedifferentiation and direct conversion, functional interactions between TFs regulating these processes are not well understood. Here we show that TFs preventing dedifferentiation are able to induce direct conversion. Using a neural lineage cell line and a large number of TFs expressed in it, we found a subset of TFs whose overexpression strongly interfered with dedifferentiation triggered by a procedure to induce induced pluripotent stem cells (iPSC), through a maintenance mechanism of the cell-type-specific transcriptional profile. Strikingly, the maintenance activity of the interfering TF set was strong enough to induce the cell line-specific transcriptional profile when overexpressed in a heterologous cell type. In addition, TFs that interfered with dedifferentiation in hepatic lineage cells involved known TFs with induction activity for hepatic lineage cells. Our results suggest that dedifferentiation suppresses a cell-type-specific transcriptional profile, which is primarily maintained by a small subset of TFs capable of inducing direct conversion. We anticipate that this functional correlation might be applicable in various cell types, which may include cancer cells, and might facilitate identification of TFs with induction activity to understand differentiation and tumorigenesis Examination of binding of 3 transcription factors and histone modifications in Neural progenitor like cells.

2013-01-01 | E-GEOD-41252 | biostudies-arrayexpress

Efficient induction of Gcm1 under folate deficiency promotes vertebrate neural development by Wnt/β-catenin pathway activation

Project description:Wnt signaling plays a major role in early neural development. An aberrant activation in Wnt/β-catenin pathway leads to defective anteroposterior patterning, resulting in neural tube closure defects (NTDs). Changes in folate metabolism may participate in early embryo fate determination. We report here that in C57BL/6C mouse embryonic stem cells (mESC), folate deficiency activates Wnt/β-catenin pathway by upregulating a chorion-specific transcription factor Gcm1. Specifically, folate deficiency promotes the formation of the Gcm1/β-catenin/T-cell factor (TCF4) complex to regulate the Wnt target gene transactivation through the Wnt-responsive elements. Moreover, the enhanced transcriptional activity of Gcm1 is found to be dependent on CREB binding protein. Lastly, in NTDs mouse models and low folate NTDs human brain samples, Gcm1 and Wnt/β-catenin target genes related to neural tube closure are specifically overexpressed. These results indicate that low folate promotes Wnt/β-catenin signaling via activating Gcm1, leading to aberrant vertebrate neural development

2018-12-27 | GSE124339 | GEO

High-resolution transcriptional analysis reveals stepwise fate conversion of supporting cells to hair cells in the chicken auditory epithelium

Project description:In contrast to mammals, the avian cochlea, specifically the basilar papilla, can regenerate sensory hair cells, which involves fate conversion of supporting cells to hair cells. To determine the mechanisms for converting supporting cells to hair cells, we used single-cell RNA sequencing during hair cell regeneration in explant cultures of chick basilar papillae. We identified dynamic changes in the gene expression of supporting cells, and the pseudotime trajectory analysis demonstrated the stepwise fate conversion from supporting cells to hair cells. Initially, supporting cell identity was erased and transition to the precursor state occurred. A subsequent gain in hair cell identity progressed together with downregulation of precursor-state genes. Transforming growth factor beta receptor 1-mediated signaling was involved in induction of the initial step, and its inhibition resulted in suppression of hair cell regeneration. Our data provide new insights for understanding fate conversion from supporting cells to hair cells in avian basilar papillae.

2023-01-10 | GSE209791 | GEO

Spatiotemporal dynamics of Bach2 orchestrates B cell responses and fate decision

Project description:The molecular circuits that direct early T-dependent B cell responses and alternative cell-fate decisions remain poorly understood. Here, we show that either B cell receptor (BCR) or CD40 signals promoted mTORC1-dependent translation of the transcription factor Bach2. Transient up-regulation of Bach2 protein restrained activated B cell expansion and differentiation into plasma cell while promoting the germinal center (GC) and memory B cell fates at the pre-GC stage. However, enforced Bach2 expression facilitated memory B cell generation versus other cell fates. Mechanistically, Bach2 limited access of AP-1 factors and formed a reciprocal repression loop with IRF4. BCR and CD40 signals also down-regulated Bach2 transcript in antigen-activated B cells, and diversified its abundance in various effector populations, predisposing Bach2 protein expression and subsequent cell-fate choices during memory recall and GC reaction. Thus signaling-induced differential dynamics of Bach2 protein and mRNA in activated B cell control their cell-fate outcomes and imprint the fate of their descendant effector cells.

2021-07-18 | GSE180277 | GEO

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