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TCF4 is a key mediator of cell identity in neuroblastoma and vulnerable to protein degradation by multiple epigenetic factors [RNA-seq]

ABSTRACT: Neuroblastomas (NBs) are aggressive pediatric tumors that are responsible for up to 15% of all pediatric cancer deaths. Two differentiation states exist in NB tumors, a majority of more committed ADRN tumor cells and a minority of neural crest cell (MES/NCC)-like cells. The transition between identity states is governed by different sets of master TFs that collectively form core regulatory circuitries (CRC) that drive high expression of downstream lineage-specific genes. In this study we aim to discover new lineage dependency factors in NB. Here, we identified the E-box transcription factor TCF4 (E2-2) not previously reported in NB to be a critical factor shared across both NB states and play important role in driving NB oncogenesis. We performed multiple functional and high-throughput analysis to delineate the unrecognized function of TCF4 in NB

ORGANISM(S): Homo sapiens

PROVIDER: GSE222212 | GEO | 2024/08/05

REPOSITORIES: GEO

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TCF4 is a key mediator of cell identity in neuroblastoma and vulnerable to protein degradation by multiple epigenetic factors [ChIP-seq]

Project description:Neuroblastomas (NBs) are aggressive pediatric tumors that are responsible for up to 15% of all pediatric cancer deaths. Two differentiation states exist in NB tumors, a majority of more committed ADRN tumor cells and a minority of neural crest cell (MES/NCC)-like cells. The transition between identity states is governed by different sets of master TFs that collectively form core regulatory circuitries (CRC) that drive high expression of downstream lineage-specific genes. In this study we aim to discover new lineage dependency factors in NB. Here, we identified the E-box transcription factor TCF4 (E2-2) not previously reported in NB to be a critical factor shared across both NB states and play important role in driving NB oncogenesis. We performed multiple functional and high-throughput analysis to delineate the unrecognized function of TCF4 in NB

2024-08-05 | GSE222213 | GEO

A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma.

Project description:Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) and mesenchymal (MES) tumor cell types, which differ in phenotype, super-enhancers (SEs) and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed the ADRN transcriptional landscape towards a MES state. A transcriptional feed-forward circuitry of NOTCH-family transcription factors amplifies the NOTCH signaling levels, explaining the swift transition between two semi-stable cellular states. This transition induces genome-wide remodeling of the H3K27ac landscape and a switch from ADRN SEs to MES SEs. Once established, the NOTCH feed-forward loop maintains the induced MES state. In vivo reprogramming of ADRN cells shows that MES and ADRN cells are equally oncogenic. Our results elucidate a swift transdifferentiation between two semi-stable epigenetic cellular states.

2019-04-18 | GSE129980 | GEO

Occupancy profiling of HAND2, MEIS2 and TCF4 by CUT&Tag from Neuroblastoma cells

Project description:HAND2, MEIS2 and TCF4 are master transcription factors (TFs) in neuroblastoma and create an interconnected core regulatory circuitry (CRC) by directly occupying each other's and their own super-enhancers (SEs), which leads to high levels of each TF expression inside the CRC. Additionally, CRC TFs cooperatively co-occupy the same SE components, which promotes the expression of genes involved in cell identity and cell-type-specific activities. Super-enhancer-mediated CRC enriched at key oncogenes in neuroblastoma. In the present study, CUT&Tag (Cleavage Under Targets and Tagmentation) analysis was performed to explore the target of HAND2, MEIS2 and TCF4 in NB cells.

2024-05-06 | GSE234337 | GEO

TCF4 germline mutation and adult-onset SHH medulloblastoma

Project description:Medulloblastoma (MB) is the most prevalent pediatric cerebral cancer, but is rare in adults. The vast majority of MB arises sporadically but some few cases occur in association with germline alterations in genes such as PTCH1, SUFU, APC, and TP53. Additional genes are responsible for MB predisposition including some that have probably not been described so far either due to the rarity of the cases and/or to the low penetrance. Here we report the case of a 27 years old woman affected by Pitt Hopkins syndrome due to a heterozygous germline pathogenic variant in TCF4 who has developed a Sonic Hedgehog (SHH)-driven MB. Somatic loss of function variants of TCF4 have been identified in SHH MB especially among adults and this case raises the question of a predisposition to late-onset SHH MB associated with TCF4 germline alteration.

2019-02-14 | GSE126545 | GEO

Cytokine stimulated keratinocytes (TCF4 KD)

Project description:In order to study the molecular mechanisms involving TCF4 in keratinocytes under different inflammatory responses, control and TCF4 knock down keratinocytes were stimulated with inflammatory cytokines and conducted RNA-seq to profile the gene expression.

2024-06-05 | GSE260642 | GEO

Complex Balanced Translocation Disrupting TCF4 and Altering TCF4 Isoform Expression Segregates as Mild Autosomal Dominant Intellectual Disability

Project description:Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. We report a three-generation family segregating mild intellectual disability with an apparently balanced chromosomal translocation t(14;18)(q23.3;q21.2) that we characterized as a complex unbalanced karyotype 46,XY,der(14)del(14)(q23.3q23.3)t(14;18)(q23.3;q21.2)del(18)(q21.2q21.2) del(18)(q21.2q21.2)inv(18)(q21.2q21.2),der(18)t(14 ;18)(q23.3;q21.2) disrupting TCF4. Using whole genome sequencing, transcriptome sequencing, qRT-PCR and nCounter analysis, we characterized the breakpoint junctions from derivative chromosomes and gene expression at the TCF4 locus. Our analyses revealed that family members segregating mild intellectual disability with the complex chromosome aberration had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Increased levels of TCF4 transcript variants originating distal to the translocation breakpoint, not the fusion transcript generated by the derivative chromosome, contributed to this increased. Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS is partially rescued by overexpression of short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain. Examination of TCF4 Isoform expression comparison between mutant and control skin fibroblast tissues

2016-05-31 | E-GEOD-77742 | biostudies-arrayexpress

TCF4 regulatory gene networks in developing dorsal telencephalon

Project description:Haplo-insufficiency of TCF4 induced by mutations or microdeletion of TCF4 gene causes Pitt-Hopkins Diseases. Recent gene association studies revealed that mutations of TCF4 is significantly associated with schizophrenia. But the role of TCF4 in developing neocortex is not known. The goal of this study is to identify TCF4 itranscriptional regulatory pathways in developing neocortex by analyzing transcriptomes of dorsal telencephalons of TCF4knockout, TCF4Heterozygote and WT littermates and comparing differential expressed genes between these genotypes.

2019-02-06 | GSE79663 | GEO

Complex Balanced Translocation Disrupting TCF4 and Altering TCF4 Isoform Expression Segregates as Mild Autosomal Dominant Intellectual Disability

2016-05-31 | GSE77742 | GEO

Cytokine stimulated keratinocytes (TCF4 KD)

Project description:Cytokine stimulated keratinocytes (TCF4 KD)

| PRJNA1082391 | ENA

Astrocyte allocation during brain development is controlled by Tcf4-mediated fate restriction

Project description:Astrocytes within specific brain regions contribute uniquely to regional circuits for higher-order brain function through interactions with local neurons. The regional diversification of astrocytes is dictated by their embryonic origin, yet the mechanisms governing their regional allocation remain unknown. Here we show that allocation of astrocytes to specific brain regions requires the transcription factor 4 (Tcf4) mediated fate restriction during brain development. Loss of Tcf4 in ventral telencephalic neural progenitors alters the fate of oligodendrocyte precursors to transient intermediate astrocyte precursor cells, resulting in mislocated astrocytes in the dorsal neocortex. These ectopic astrocytes originated from the ventral telencephalon engage with neurons and acquire features reminiscent of local neocortical astrocytes. Furthermore, Tcf4 functions as a suppressor of astrocyte fate during differentiation of oligodendrocyte precursors, thereby restricting the fate to oligodendrocyte lineage. Our study reveals that fate restriction governs regional astrocyte allocation, contributing to astrocyte diversification across brain regions.

2024-08-14 | GSE244709 | GEO

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