The transcription factor Deaf-1 modulates Engrailed-1 expression to regulate the specification of skin appendage fate
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE129965 | GEO | 2019/07/01
REPOSITORIES: GEO
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Project description:Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, we report that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating a role in the cellular response to the stimulation of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. Our findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.
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Project description:Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, we report that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating a role in the cellular response to the stimulation of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. Our findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.
2023-12-19 | GSE228802 | GEO
Project description:Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases including systemic sclerosis. Here we show that Engrailed 1 (EN1) is re-expressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and, in turn, EN1 mediates the pro-fibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a pro-fibrotic gene expression profile functionally related to the cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP-transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the re-organization of cytoskeleton during myofibroblast differentiation both in standard fibroblast culture systems and in in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.
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Project description:Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases including systemic sclerosis. Here we show that Engrailed 1 (EN1) is re-expressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and, in turn, EN1 mediates the pro-fibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a pro-fibrotic gene expression profile functionally related to the cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP-transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the re-organization of cytoskeleton during myofibroblast differentiation both in standard fibroblast culture systems and in in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.
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Project description:A key pathological feature of Parkinson’s Disease (PD) is the progressive degeneration of dopaminergic neurons (DAns) in the substantia nigra pars compacta. Considering the major role of EN1 in the development and maintenance of these DAns and the implications from En1 mouse models, it is highly interesting to study the molecular and protective effect of EN1 also in a human cellular model. Therefore, we generated EN1 knock-out (ko) human induced pluripotent stem cell (hiPSCs) lines and analyzed these during neuronal differentiation. Although the EN1 ko didn’t interfere with neuronal differentiation and generation of TH+ neurons per se, the neurons exhibited shorter neurites. Furthermore, mitochondrial respiration, as well as mitochondrial complex I abundance was significantly reduced in fully differentiated neurons. To understand the implications of an EN1 ko during differentiation, we performed a transcriptome analysis of human neuronal precursor cells (hNPCs) which unveiled alterations in cilia-associated pathways. Further analysis of ciliary morphology revealed an elongation of primary cilia in EN1-deficient hNPCs. Besides, also Wnt signaling pathways were severely affected. Upon stimulating hNPCs with Wnt which drastically increased EN1 expression in WT lines, the phenotypes concerning mitochondrial function and cilia were exacerbated in EN1 ko hNPCs. They failed to enhance the expression of the complex I subunits NDUFS1 and 3, and now displayed a reduced mitochondrial respiration. Furthermore, Wnt stimulation decreased ciliogenesis in EN1 ko hNPCs but increased ciliary length even further. This further highlights the relevance of primary cilia next to mitochondria for the functionality and correct maintenance of human DAns and provides new possibilities to establish neuroprotective therapies for PD.
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Project description:Engrailed 1 (EN1) is a conserved transcription factor essential for programming, survival, and maintenance of midbrain dopaminergic neurons. En1-hemizygosity (En1+/-) leads to a spontaneous Parkinson’s disease-like (PD-like) progressive nigrostriatal degeneration as well as motor impairment and depressive-like behavior in SwissOF1 (OF1-En1+/-) mice. This phenotype is absent in C57Bl/6j (C57-En1+/-) mice. Here we studied PD-like phenotypes and early transcriptome profiles in OF1 wild-type (WT) and OF1-En1+/- male mice and compare to that of C57 WT and C57-En1+/- male mice. To detect transcriptional changes prior to dopaminergic cell loss, we performed RNA-seq of 1-week old mice substantia nigra pars compacta (SNpc). Histology and stereology were used to assess dopaminergic nigrostriatal pathology in 4 and 16 weeks old mice. OF1-En1+/- mice showed an increase (79%) in dopaminergic striatal axonal swellings from 4 to 16 weeks and a loss (23%) of dopaminergic neurons in the SNpc at 16 weeks compared to OF1 WT. Axonal swellings were also present in C57-En1+/- mice but did not increase over time. 52 differentially expressed genes (DEGs) were observed between the C57-WT and the C57-En1+/- mice, while 198 DEGs were observed in the OF1 strain. Enrichment analysis revealed that the neuroprotective phenotype of C57-En1+/- mice was associated with an upregulation of oxidative phosphorylation-related genes compared to both C57 WT and to OF1- En1+/- mice. These results highlight the importance of considering genetic background in PD models and provide valuable insight on how expression of mitochondrial proteins before the onset of neurodegeneration is associated to vulnerability of nigrostriatal dopaminergic neurons.
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Project description:Long non-coding RNAs (lncRNAs) can be important components in gene regulatory networks1, but we are only beginning to understand the nature and extent of their involvement in human Mendelian disease. Here we show that deletions of an unannotated lncRNA locus on human chromosome 2 cause a severe congenital limb malformation. Using exome sequencing and array CGH, we identified homozygous 27-63 kb deletions located 300 kb upstream of the engrailed-1 (EN1) gene in patients with a complex limb malformation, featuring mesomelic shortening, syndactyly, and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of limb-specific En1 expression and a double dorsal limb phenotype, recapitulating the human malformation. Genome-wide analysis in the developing mouse limb revealed the presence of a 4-exon long non-coding transcript within the deleted region, which we named Maenli (for Master activator of En1 in the limb). Functional dissection of the Maenli locus showed that limb-specific En1 expression depends on transcription of Maenli and its loss resulted in the double dorsal limb phenotype. Concomitant monoallelic inactivation of En1 and Maenli in double heterozygous mice did not rescue the limb phenotype, indicating that En1 activation in the limb requires the cis-acting regulatory element Maenli. Moreover, our results strongly suggest that En1 activation is dependent on Maenli transcription, but not on the Maenli RNA itself. Thus, Maenli expression in the limb acts in cis to promote En1 transcriptional activation; its loss results in congenital malformation of the limbs, a subset of the full En1 associated phenotype. Together, our findings provide evidence that mutations involving lncRNAs loci can result in human Mendelian disease.
2020-10-25 | GSE149368 | GEO
Project description:Long non-coding RNAs (lncRNAs) can be important components in gene regulatory networks1, but we are only beginning to understand the nature and extent of their involvement in human Mendelian disease. Here we show that deletions of an unannotated lncRNA locus on human chromosome 2 cause a severe congenital limb malformation. Using exome sequencing and array CGH, we identified homozygous 27-63 kb deletions located 300 kb upstream of the engrailed-1 (EN1) gene in patients with a complex limb malformation, featuring mesomelic shortening, syndactyly, and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of limb-specific En1 expression and a double dorsal limb phenotype, recapitulating the human malformation. Genome-wide analysis in the developing mouse limb revealed the presence of a 4-exon long non-coding transcript within the deleted region, which we named Maenli (for Master activator of En1 in the limb). Functional dissection of the Maenli locus showed that limb-specific En1 expression depends on transcription of Maenli and its loss resulted in the double dorsal limb phenotype. Concomitant monoallelic inactivation of En1 and Maenli in double heterozygous mice did not rescue the limb phenotype, indicating that En1 activation in the limb requires the cis-acting regulatory element Maenli. Moreover, our results strongly suggest that En1 activation is dependent on Maenli transcription, but not on the Maenli RNA itself. Thus, Maenli expression in the limb acts in cis to promote En1 transcriptional activation; its loss results in congenital malformation of the limbs, a subset of the full En1 associated phenotype. Together, our findings provide evidence that mutations involving lncRNAs loci can result in human Mendelian disease.
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Project description:Long non-coding RNAs (lncRNAs) can be important components in gene regulatory networks1, but we are only beginning to understand the nature and extent of their involvement in human Mendelian disease. Here we show that deletions of an unannotated lncRNA locus on human chromosome 2 cause a severe congenital limb malformation. Using exome sequencing and array CGH, we identified homozygous 27-63 kb deletions located 300 kb upstream of the engrailed-1 (EN1) gene in patients with a complex limb malformation, featuring mesomelic shortening, syndactyly, and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of limb-specific En1 expression and a double dorsal limb phenotype, recapitulating the human malformation. Genome-wide analysis in the developing mouse limb revealed the presence of a 4-exon long non-coding transcript within the deleted region, which we named Maenli (for Master activator of En1 in the limb). Functional dissection of the Maenli locus showed that limb-specific En1 expression depends on transcription of Maenli and its loss resulted in the double dorsal limb phenotype. Concomitant monoallelic inactivation of En1 and Maenli in double heterozygous mice did not rescue the limb phenotype, indicating that En1 activation in the limb requires the cis-acting regulatory element Maenli. Moreover, our results strongly suggest that En1 activation is dependent on Maenli transcription, but not on the Maenli RNA itself. Thus, Maenli expression in the limb acts in cis to promote En1 transcriptional activation; its loss results in congenital malformation of the limbs, a subset of the full En1 associated phenotype. Together, our findings provide evidence that mutations involving lncRNAs loci can result in human Mendelian disease.
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Project description:Long non-coding RNAs (lncRNAs) can be important components in gene regulatory networks1, but we are only beginning to understand the nature and extent of their involvement in human Mendelian disease. Here we show that deletions of an unannotated lncRNA locus on human chromosome 2 cause a severe congenital limb malformation. Using exome sequencing and array CGH, we identified homozygous 27-63 kb deletions located 300 kb upstream of the engrailed-1 (EN1) gene in patients with a complex limb malformation, featuring mesomelic shortening, syndactyly, and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of limb-specific En1 expression and a double dorsal limb phenotype, recapitulating the human malformation. Genome-wide analysis in the developing mouse limb revealed the presence of a 4-exon long non-coding transcript within the deleted region, which we named Maenli (for Master activator of En1 in the limb). Functional dissection of the Maenli locus showed that limb-specific En1 expression depends on transcription of Maenli and its loss resulted in the double dorsal limb phenotype. Concomitant monoallelic inactivation of En1 and Maenli in double heterozygous mice did not rescue the limb phenotype, indicating that En1 activation in the limb requires the cis-acting regulatory element Maenli. Moreover, our results strongly suggest that En1 activation is dependent on Maenli transcription, but not on the Maenli RNA itself. Thus, Maenli expression in the limb acts in cis to promote En1 transcriptional activation; its loss results in congenital malformation of the limbs, a subset of the full En1 associated phenotype. Together, our findings provide evidence that mutations involving lncRNAs loci can result in human Mendelian disease.
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