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Single-cell epigenome analysis identifies transcriptional events controlling direct conversion of human fibroblasts to pancreatic ductal-like cells [ChIP-seq]

ABSTRACT: Cell fate can be reprogrammed by ectopic expression of lineage-specific transcription factors (TF). However, the exact cell state transitions during transdifferentiation are still poorly understood. Here, we have generated pancreatic exocrine cells of ductal epithelial identity from human fibroblasts using a set of six TFs. We mapped the molecular determinants of lineage dynamics using a factor-indexing method based on single-nuclei multiome sequencing (FI-snMultiome-seq) that enables dissecting the role of each individual TF and pool of TFs in cell fate conversion. We show that transition from mesenchymal fibroblast identity to epithelial pancreatic exocrine fate involves two deterministic steps: an endodermal progenitor state defined by activation of HHEX with FOXA2 and SOX17, and a temporal GATA4 activation essential for maintenance of pancreatic cell fate program. Collectively, our data suggest that transdifferentiation – although being considered a direct cell fate conversion method – occurs through transient progenitor states orchestrated by stepwise activation of distinct TFs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216857 | GEO | 2023/08/14

REPOSITORIES: GEO

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Single-cell epigenome analysis identifies transcriptional events controlling direct conversion of human fibroblasts to pancreatic ductal-like cells [RNA-seq]

Project description:Cell fate can be reprogrammed by ectopic expression of lineage-specific transcription factors (TF). However, the exact cell state transitions during transdifferentiation are still poorly understood. Here, we have generated pancreatic exocrine cells of ductal epithelial identity from human fibroblasts using a set of six TFs. We mapped the molecular determinants of lineage dynamics using a factor-indexing method based on single-nuclei multiome sequencing (FI-snMultiome-seq) that enables dissecting the role of each individual TF and pool of TFs in cell fate conversion. We show that transition from mesenchymal fibroblast identity to epithelial pancreatic exocrine fate involves two deterministic steps: an endodermal progenitor state defined by activation of HHEX with FOXA2 and SOX17, and a temporal GATA4 activation essential for maintenance of pancreatic cell fate program. Collectively, our data suggest that transdifferentiation – although being considered a direct cell fate conversion method – occurs through transient progenitor states orchestrated by stepwise activation of distinct TFs.

2023-08-14 | GSE216854 | GEO

Single-cell epigenome analysis identifies transcriptional events controlling direct conversion of human fibroblasts to pancreatic ductal-like cells [FI-snMultiome-seq]

2023-08-14 | GSE216858 | GEO

Single-cell epigenome analysis identifies transcriptional events controlling direct conversion of human fibroblasts to pancreatic ductal-like cells [ATAC-seq]

2023-08-14 | GSE216855 | GEO

Dynamic regulation of chromatin accessibility and transcription factors underlies distinct organ identity and function

Project description:After gut tube closure, different regional domains develop into uniquely functional organs. Our single cell analysis demonstrates that chromatin accessibility predicts lineage fate decisions, reflecting the transcriptional profiles of individual cells. Combining with bulk analyses, we have generated a comprehensive map of epigenetic changes over developmental time, revealing how chromatin accessibility and transcription factor (TF) binding cooperate to control organ identity and differentiation. Loss of the foregut and hindgut lineage-specific TFs, Sox2 and Cdx2, leads to the acquisition of accessibility profiles similar to neighbouring organs, while Sox2 overexpression in early development induces a loss of intestinal identity and pancreatic transformation into foregut fate precursors. Moreover, ectopic expression of Sox2 in normal adult and cancer intestinal and pancreatic tissues leads to lineage alterations, demonstrating its critical role in homeostasis and cancer. Together, these studies define the chromatin and transcriptional mechanisms of organ identity and lineage plasticity in development and disease.

2022-03-27 | GSE168373 | GEO

Transcription factors harbor functional RNA-binding domains

Project description:Transcription factors (TFs) orchestrate the gene expression programs that define each cell’s identity, and the canonical TF accomplishes this with two functional domains1–7. The DNA-binding domain interacts with specific genomic sequences, and the effector domain binds coactivators or co-repressors that contribute to transcriptional regulation. We report here that TFs also frequently contain an RNA-binding domain and that this also contributes to gene regulation. Nearly half of TFs in human cells show evidence of RNA-binding and their affinities for RNA are similar to those of well-studied RNA-binding proteins. The RNA-binding sites of TFs have sequence and functional features analogous to the arginine-rich motif of the HIV transcriptional activator Tat8,9. RNA-binding contributes to TF function by promoting the dynamic association of TFs with chromatin. We conclude that the canonical definition of transcription factors is incomplete, and that the ability of many TFs to bind DNA, RNA and protein is fundamental to gene regulation.

2023-07-02 | PXD035484 | Pride

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

KLF4 binding is involved in the organization and regulation of 3D enhancer networks during acquisition and maintenance of pluripotency.

Project description:Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified by reprogramming somatic cells to pluripotent stem cells (PSCs) via expression of OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their target gene loci in a temporal manner remains incompletely understood. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and its association to 3D enhancer rewiring and transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts (MEFs) to PSCs. Inducible depletion of KLF factors in PSCs caused a genome-wide decrease in the connectivity of enhancers, while disruption of individual KLF4 binding sites from PSC-specific enhancers was sufficient to impair enhancer-promoter contacts and reduce expression of associated genes. Our study provides an integrative view of the complex activities of a lineage-specifying TF during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding.

2019-09-03 | PXD014631 | Pride

A single cell-based computational platform to identify chemical compounds targeting desired sets of transcription factors for cellular conversion [Single-cell RNA-seq]

Project description:Conversion of cellular identity can be achieved safely, without genetic manipulation, by inducing signalling perturbations with chemical compounds to target cell fate-governing transcription factors (TFs). However, chemical-induced cellular conversion currently requires large-scale screening of small compounds, which is time- and labour-intensive. There are no existing computational approaches that facilitate chemical conversion of cell fate. Here, we develop a computational framework (SiPer) to systematically predict chemical compounds specifically targeting desired sets of TFs to direct cellular conversion. This framework integrates a large compendium of chemical perturbation datasets with a network model. We show that SiPer is generally applicable to diverse cellular conversion examples, recapitulating the known chemical compounds and their corresponding protein targets. Furthermore, using chemical compounds predicted by SiPer, we develop a highly efficient protocol for the generation of functional human induced hepatocytes (hiHeps). These results demonstrate that SiPer provides a valuable resource to efficiently identify chemical compounds for cellular conversion.

2022-11-17 | GSE162909 | GEO

Pioneer transcription factors coordinate active and repressive gene expression states to regulate cell fate [CUT&Run and ChIP-seq]

Project description:Pioneer transcription factors (TFs) regulate cell fate by establishing transcriptionally primed and active states. However, cell fate control requires the coordination of both lineage-specific gene activation and repression of alternative lineage programs, a process that is poorly understood. Here, we demonstrate that the pioneer TF Forkhead box A (FOXA), required for endoderm lineage commitment, coordinates with the PR domain zinc finger 1 (PRDM1) TF to recruit Polycomb repressive complexes, which establish bivalent enhancers and repress alternative lineage programs. Similarly, the pioneer TF OCT4 coordinates with PRDM14 to repress cell differentiation programs in pluripotent stem cells, suggesting this is a common feature of pioneer TFs. We propose that pioneer and PRDM TFs coordinate recruitment of Polycomb complexes to safeguard cell fate.

2024-01-10 | GSE215434 | GEO

Pioneer transcription factors coordinate active and repressive gene expression states to regulate cell fate [RNA-seq]

2024-01-10 | GSE215435 | GEO

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