Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

An integrative CRISPR screen reveals the AP-1 transcription factor complex mediates activation of the human neural crest cell gene regulatory program

ABSTRACT: The complex interplay between signaling systems, transcription factors, and cis-regulatory elements required for development are encoded within gene regulatory networks (GRN). Although GRNs have greatly expanded our understanding of cell fate decisions during embryogenesis, they are typically assembled via a candidate-based approach, which fails to consider the tissue specific functions more broadly expressed TFs may employ. To address this, we combined a TF-focused CRISPR screen with epigenomic and transcriptional profiling of human neural crest cells. This approach unbiasedly identified several key regulators of human neural crest cell development, including the ubiquitous AP-1 transcription factor complex. Functional characterization of AP-1 demonstrated it is a major regulator of neural crest identity, working with the cell type specific TF, TFAP2A, to shape the neural crest epigenome. Interestingly, overexpression of AP-1 and TFAP2A in human embryonic stem cells is sufficient to drive neural crest identity, suggesting a critical role for AP-1 in the transition from pluripotency to more specialized stem cell states. Furthermore, we demonstrate that AP-1 serves as a nuclear effector of FGF/MAPK signaling in human neural crest cells, a previously missing link between FGF signaling and neural crest development. Our results demonstrate signaling effectors carry out cell-type specific enhancer selection and may contribute to our efforts in engineering neural crest cells for the purpose of tissue repair and regeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212793 | GEO | 2023/08/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Sumoylation Pathway Is Required to Maintain the Basal Breast Cancer Subtype

Project description:This study is an attempt to characterize the molecular basis for the functional differences between TFAP2A and TFAP2C. Recent findings have highlighted a critical role for the TFAP2C (AP-2M-NM-3) transcription factor in maintaining the luminal phenotype through the regulation of luminal-associated genes. Of particular interest is that the highly homologous AP-2 family member, TFAP2A (AP-2M-NM-1), is expressed in luminal breast cancer but appears to have a functionally distinct role in gene regulation. There is 83% similarity between TFAP2A and TFAP2C with 76% identity in the carboxyl-half of the proteins containing the DNA binding and dimerization domains. Although the two family members appear to have complementary and overlapping roles in regulating neural crest development, they have clear functional differences with regard to regulation of ERM-NM-1 expression. The global genomic binding pattern for TFAP2A and TFAP2C is highly similar. Genomic binding for TFAP2A and TFAP2C in the regulatory region for luminal-associated genes further demonstrated co-localization of the two factors. On the other hand, clear functional differences exist when comparing the effect on the pattern of gene expression following knockdown of TFAP2A vs. TFAP2C. In each case, knockdown of TFAP2C resulted in an abrogation of expression (RNA and protein) of the luminal-associated gene, whereas, knockdown of TFAP2A had minimal or no effect. By contrast, a known TFAP2A target gene, CDKN1A, was responsive to TFAP2A only. 1 ChIP-Seq data for TFAP2A in human breast carcinoma cell line MCF-7. See associated publication.

2014-04-12 | E-GEOD-44257 | biostudies-arrayexpress

Sumoylation Pathway Is Required to Maintain the Basal Breast Cancer Subtype

Project description:This study is an attempt to characterize the molecular basis for the functional differences between TFAP2A and TFAP2C. Recent findings have highlighted a critical role for the TFAP2C (AP-2γ) transcription factor in maintaining the luminal phenotype through the regulation of luminal-associated genes. Of particular interest is that the highly homologous AP-2 family member, TFAP2A (AP-2α), is expressed in luminal breast cancer but appears to have a functionally distinct role in gene regulation. There is 83% similarity between TFAP2A and TFAP2C with 76% identity in the carboxyl-half of the proteins containing the DNA binding and dimerization domains. Although the two family members appear to have complementary and overlapping roles in regulating neural crest development, they have clear functional differences with regard to regulation of ERα expression. The global genomic binding pattern for TFAP2A and TFAP2C is highly similar. Genomic binding for TFAP2A and TFAP2C in the regulatory region for luminal-associated genes further demonstrated co-localization of the two factors. On the other hand, clear functional differences exist when comparing the effect on the pattern of gene expression following knockdown of TFAP2A vs. TFAP2C. In each case, knockdown of TFAP2C resulted in an abrogation of expression (RNA and protein) of the luminal-associated gene, whereas, knockdown of TFAP2A had minimal or no effect. By contrast, a known TFAP2A target gene, CDKN1A, was responsive to TFAP2A only.

2014-04-12 | GSE44257 | GEO

Chicken neural crest and neural plate

Project description:Neural cest cells are a transient stem cell-like population appearing during vertebrate embryonic development. Generation of the cranial neural crest is known to require a balanced combination of FGF and BMP levels. However, it is poorly understood how the functions of such growth factors are controlled in the extracellular spaces. Anosmin is an extracellular matrix protein implicated in FGF signaling and mutated in Kallmann syndrome. Here, we demonstrate that anosmin (Gga.14976.1.S1_at, clone ChEST132d10) is synthesized locally in the cranial neural crest of chicken embryos and is essential for cranial neural crest formation. Anosmin upregulates FGF8 and BMP5 gene expression; it also enhances FGF8 activity while inhibiting BMP5 and WNT3a signaling. Taken together, our data establish that the matrix protein anosmin is required for cranial neural crest formation, with funtional modulation of FGF, BMP, and WNT.

2012-06-01 | GSE38381 | GEO

Heterodimerization of Tfap2 pioneer factors drives epigenomic remodeling during neural crest specification

Project description:Cell fate commitment is a stepwise process, in which multipotent progenitors transition through sequential regulatory states as they become fate restricted. Recent studies have highlighted the extensive transcriptomic shifts that typify cell differentiation, but our understanding of the epigenetic mechanisms underlying these changes is still superficial. To examine how chromatin states are reorganized during cell fate commitment in an in vivo system, we examined the function of pioneer factor Tfap2a at discrete stages of neural crest development. Our results show that TFAP2a activates distinct sets of genomic regions during induction and specification of neural crest cells. Genomic occupancy analysis revealed that the repertoire of TFAP2a targets depends upon its dimerization with paralogous proteins TFAP2c and TFAP2b. During gastrula stages, TFAP2a/c heterodimers activate components of the neural plate border induction program. As neurulation begins, TFAP2a trades partners, and TFAP2a/b heterodimers reorganize the epigenomic landscape of progenitor cells to promote neural crest specification. We propose that this molecular switch acts to drive progressive cell commitment, remodeling the epigenomic landscape to define the presumptive neural crest. Our findings show how pioneer factors regulate distinct genomic targets in a stage-specific manner, and highlight how paralogy can serve as an evolutionary strategy to diversify the function of the regulators that control embryonic development.

2019-12-12 | GSE126880 | GEO

Identification of Lrig3 target genes in Xenopus animal caps injected with wnt3a and chordin

Project description:During embryonic development, the neural crest is a transient, migratory cell population that differentiates into a large variety of tissues and contributes much to the formation of vertebrate body. In Xenopus, lrig3 is involved in neural crest formation by modulating FGF and Wnt signaling. Lrig3 functions downstream of pax3 and zic1 to regulate the expression of neural crest markers. We used microarrays to identify the lrig3 target genes during neural crest formation.

2014-09-01 | GSE50487 | GEO

Post-transcriptional tuning of FGF signaling mediates neural crest induction

Project description:Ectodermal patterning is required for the establishment of multiple components of the vertebrate body plan. Previous studies have demonstrated that precise combinations of extracellular signals determine the induction of neural or neural crest progenitors. Yet, we still have a limited understanding of how the response to inductive signals is optimized to generate the proper transcriptional output in target cells. Here we show that post-transcriptional attenuation of signaling gradients is essential for the formation of the neural crest. We found that neural crest cells display enhanced expression of Dicer, which promotes the maturation of a set of cell-type-specific miRNAs. These miRNAs target multiple components of the FGF signaling pathway, a central player in the process of neural induction in avian embryos. Loss of neural crest miRNAs prevented the attenuation of this neuralizing signal, leading to the expansion of the neural plate at the expense of neural crest cells. Thus, the post-transcriptional attenuation of FGF signaling is pre-requisite for neural crest specification. These findings demonstrate how post-transcriptional repression may reshape signaling gradients to set the boundaries between distinct spatial domains of progenitor cells.

2020-12-07 | GSE150007 | GEO

A chemical screen in zebrafish embryonic cells establishes that Akt activation is required for neural crest development [RNA-seq]

Project description:The neural crest is a dynamic progenitor cell population that arises at the border of neural and non-neural ectoderm. The inductive roles of FGF, Wnt, and BMP at the neural plate border are well established, but the signals required for subsequent neural crest development remain poorly characterized. Here, we conducted a screen in primary zebrafish embryo cultures for chemicals that decrease neural crest formation, as read out by crestin:EGFP expression. We found that the natural product caffeic acid phenethyl ester (CAPE) disrupts neural crest gene expression, migration, and melanocytic differentiation by reducing Sox10 activity. CAPE inhibits PI3K/Akt signaling specifically in FGF-stimulated cells, and neural crest defects in CAPE-treated embryos are suppressed by constitutively active Akt1. Inhibition of Akt activity by constitutively active PTEN similarly decreases crestin expression and Sox10 activity. Our study has identified Akt as a novel intracellular pathway required for neural crest development.

2017-08-17 | GSE95814 | GEO

A chemical screen in zebrafish embryonic cells establishes that Akt activation is required for neural crest development [ATAC-seq]

2017-08-17 | GSE95813 | GEO

CUT&RUN profiling of Tfap2a binding genome-wide using zebrafish embryos at 24hpf

Project description:The purpose of this study was to identify Tfap2a binding genome-wide in zebrafish embryos at 24hpf. Tfap2 transcription factors are essential regulators of neural crest development, melanocyte differentiation, and melanoma progression. We aimed to identify Tfap2a-occupied genes to determine direct Tfap2a-regulated transcriptional networks.

2023-12-18 | GSE250450 | GEO

TFAP2 paralogs regulate midfacial development in part through a conserved ALX genetic pathway [scRNA-seq]

Project description:Cranial neural crest development is governed by positional gene regulatory networks (GRNs). Fine-tuning of the GRN components underly facial shape variation, yet how those in the midface are connected and activated remain poorly understood. Here, we show that concerted inactivation of Tfap2a and Tfap2b in the murine neural crest, even during the late migratory phase, results in a midfacial cleft and skeletal abnormalities. Bulk and single-cell RNA-seq profiling reveal that loss of both Tfap2 members dysregulates numerous midface GRN components involved in midface morphogenesis, patterning, and differentiation. Notably, Alx1/3/4 (Alx) transcript levels are reduced, while ChIP-seq analyses suggest TFAP2 directly and positively regulates Alx gene expression. TFAP2 and ALX co-expression in midfacial neural crest cells of both mouse and zebrafish further implies conservation of this regulatory axis across vertebrates. Consistent with this notion in zebrafish, tfap2a mutants present abnormal alx3 expression patterns, Tfap2a binds alx loci, and tfap2a-alx3 genetic interactions are observed. Together, these data demonstrate TFAP2 paralogs regulate vertebrate midfacial development by activating expression of ALX transcription factors.

2024-01-01 | GSE246806 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data