Mus musculus
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ABSTRACT:
PROVIDER: PRJNA135019 | ENA |
REPOSITORIES: ENA
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Project description:Dominant mutations in cardiac transcription factor genes cause human inherited congenital heart defects (CHDs), but their molecular basis is not understood. Transcription factors and Brg1/Brm-associated factor (BAF) chromatin remodeling complex interactions suggest potential mechanisms, but the role of BAF complexes in cardiogenesis is not known. Here we show that dosage of Brg1 is critical for mouse and zebrafish cardiogenesis. Disrupting the balance between Brg1 and disease-causing cardiac transcription factors, including Tbx5, Tbx20, and Nkx2-5, causes severe cardiac anomalies, revealing an essential allelic balance between Brg1 and these cardiac transcription factor genes. This suggests that relative levels of transcription factors and BAF complexes are important for heart development, which is supported by reduced occupancy of Brg1 at cardiac genes in Tbx5 haploinsufficient hearts. Our results reveal complex dosage-sensitive interdependence between transcription factors and BAF complexes, providing a potential mechanism underlying transcription factor haploinsufficiency, with implications for multigenic inheritance of CHDs. We performed transcriptional profiling of E11.5 hearts from mice heterozygous for deletions of Brg1, Tbx5, or Nkx2-5, and mice that were compound heterozygotes for Brg1 and each transcription factor gene (Tbx5 and Nkx2-5).
2010-12-22 | E-GEOD-26191 | biostudies-arrayexpress
Project description:Dominant mutations in cardiac transcription factor genes cause human inherited congenital heart defects (CHDs), but their molecular basis is not understood. Transcription factors and Brg1/Brm-associated factor (BAF) chromatin remodeling complex interactions suggest potential mechanisms, but the role of BAF complexes in cardiogenesis is not known. Here we show that dosage of Brg1 is critical for mouse and zebrafish cardiogenesis. Disrupting the balance between Brg1 and disease-causing cardiac transcription factors, including Tbx5, Tbx20, and Nkx2-5, causes severe cardiac anomalies, revealing an essential allelic balance between Brg1 and these cardiac transcription factor genes. This suggests that relative levels of transcription factors and BAF complexes are important for heart development, which is supported by reduced occupancy of Brg1 at cardiac genes in Tbx5 haploinsufficient hearts. Our results reveal complex dosage-sensitive interdependence between transcription factors and BAF complexes, providing a potential mechanism underlying transcription factor haploinsufficiency, with implications for multigenic inheritance of CHDs.
2010-12-22 | GSE26191 | GEO
Project description:Suspended animation (e.g. hibernation, diapause) allows organisms to survive extreme environments. But the mechanisms underlying the evolution of suspended animation states are unknown. The African turquoise killifish has evolved diapause as a form of suspended development to survive the complete drought that occurs every summer. Here, we show that gene duplicates – paralogs – exhibit specialized expression in diapause compared to normal development in the African turquoise killifish. Surprisingly, paralogs with specialized expression in diapause are evolutionarily very ancient and are present even in vertebrates that do not exhibit diapause. To determine if evolution of diapause is due to the regulatory landscape rewiring at ancient paralogs, we assessed chromatin accessibility genome-wide in fish species with or without diapause. This analysis revealed an evolutionary recent increase in chromatin accessibility at very ancient paralogs in African turquoise killifish. The increase in chromatin accessibility is linked to the presence of new binding sites for transcription factors, likely due to de novo mutations and transposable element (TE) insertion. Interestingly, accessible chromatin regions in diapause are enriched for lipid metabolism genes, and our lipidomics studies uncover a striking difference in lipid species in African turquoise killifish diapause, which could be critical for long-term survival. Together, our results show that diapause likely originated by repurposing pre-existing gene programs via recent changes in the regulatory landscape. This work raises the possibility that suspended animation programs could be reactivated in other species for long-term preservation via transcription factor remodeling and suggests a mechanism for how complex adaptations evolve in nature.
2021-08-05 | ST001898 | MetabolomicsWorkbench
Project description:Chromatin plays a crucial role in the intermediation between cell signaling and gene expression. The nucleolus is sensitive to stress and can orchestrate a chain of cellular events in response to stress signals. Despite being a growth factor, FGF2 has anti-proliferative and tumor-suppressive functions in some cellular contexts. In this work, we investigated how the antiproliferative effect of FGF2 modulates chromatin, nucleolus, and rDNA-associated proteins. The chromatin and nucleolar proteome indicated that FGF2 stimulation modulates proteins related to transcription regulation, particularly rRNA expression, and chromatin remodeling proteins. Upon 24 hrs of FGF2 stimulation, the global transcriptional rate and nucleolus area increased in associationalong with intense nucleolar disorganization detected by fibrillarin dispersion and electron microscopy analyses. We confirmed that FGF2 stimulation induced immature rRNA accumulation by increasing rRNA transcription regardless of changes in ribosome profiling. The rDNA-associated protein analysis reinforced that FGF2 stimulus interferes with transcription and rRNA processing/modification, since the proteins Nolc1 and Tcof1 are were upregulated after FGF2 stimulation. Changes in rRNA expression may be crucial for triggering the antiproliferative effect induced by FGF2 since inhibiting RNA Pol I, responsible for rRNA expression, partially reversed the growth arrest induced by FGF2. Taken together, we demonstrate that the antiproliferative FGF2 stimulus triggers significant transcriptional changes, and modulation modulates of the main cell transcription site, the nucleolus, directly modulating the proteome of the rDNA loci.
2022-10-12 | MSV000090518 | MassIVE
Project description:Chromatin plays a crucial role in the intermediation between cell signaling and gene expression. The nucleolus is sensitive to stress and can orchestrate a chain of cellular events in response to stress signals. Despite being a growth factor, FGF2 has anti-proliferative and tumor-suppressive functions in some cellular contexts. In this work, we investigated how the antiproliferative effect of FGF2 modulates chromatin, nucleolus, and rDNA-associated proteins. The chromatin and nucleolar proteome indicated that FGF2 stimulation modulates proteins related to transcription regulation, particularly rRNA expression, and chromatin remodeling proteins. Upon 24 hrs of FGF2 stimulation, the global transcriptional rate and nucleolus area increased in associationalong with intense nucleolar disorganization detected by fibrillarin dispersion and electron microscopy analyses. We confirmed that FGF2 stimulation induced immature rRNA accumulation by increasing rRNA transcription regardless of changes in ribosome profiling. The rDNA-associated protein analysis reinforced that FGF2 stimulus interferes with transcription and rRNA processing/modification, since the proteins Nolc1 and Tcof1 are were upregulated after FGF2 stimulation. Changes in rRNA expression may be crucial for triggering the antiproliferative effect induced by FGF2 since inhibiting RNA Pol I, responsible for rRNA expression, partially reversed the growth arrest induced by FGF2. Taken together, we demonstrate that the antiproliferative FGF2 stimulus triggers significant transcriptional changes, and modulation modulates of the main cell transcription site, the nucleolus, directly modulating the proteome of the rDNA loci.
2022-10-12 | MSV000090516 | MassIVE
Project description:Chromatin plays a crucial role in the intermediation between cell signaling and gene expression. The nucleolus is sensitive to stress and can orchestrate a chain of cellular events in response to stress signals. Despite being a growth factor, FGF2 has anti-proliferative and tumor-suppressive functions in some cellular contexts. In this work, we investigated how the antiproliferative effect of FGF2 modulates chromatin, nucleolus, and rDNA-associated proteins. The chromatin and nucleolar proteome indicated that FGF2 stimulation modulates proteins related to transcription regulation, particularly rRNA expression, and chromatin remodeling proteins. Upon 24 hrs of FGF2 stimulation, the global transcriptional rate and nucleolus area increased in associationalong with intense nucleolar disorganization detected by fibrillarin dispersion and electron microscopy analyses. We confirmed that FGF2 stimulation induced immature rRNA accumulation by increasing rRNA transcription regardless of changes in ribosome profiling. The rDNA-associated protein analysis reinforced that FGF2 stimulus interferes with transcription and rRNA processing/modification, since the proteins Nolc1 and Tcof1 are were upregulated after FGF2 stimulation. Changes in rRNA expression may be crucial for triggering the antiproliferative effect induced by FGF2 since inhibiting RNA Pol I, responsible for rRNA expression, partially reversed the growth arrest induced by FGF2. Taken together, we demonstrate that the antiproliferative FGF2 stimulus triggers significant transcriptional changes, and modulation modulates of the main cell transcription site, the nucleolus, directly modulating the proteome of the rDNA loci.
2022-10-11 | MSV000090511 | MassIVE
Project description:The transcription factor CCCTC-binding factor (CTCF) modulates pleiotropic functions mostly related to gene expression regulation. The role of CTCF in large scale genome organization is also well established. A unifying model to explain relationships between many CTCF-mediated activities involve direct or indirect interactions with numerous protein cofactors recruited to specific binding sites. The co-association of CTCF with other architectural proteins such as cohesin, chromodomain helicases and BRG1 further support the interplay between master regulators of mammalian genome folding. Here we report a comprehensive LC-MS/MS mapping of the components of the SWI/SNF chromatin remodeling complex co-associated with CTCF including subunits belonging to the core, signature and ATPase modules. We further show that the localization patterns of representative SWI/SNF members significantly overlap with CTCF sites on transcriptionally active chromatin regions. Moreover, we provide evidence of a direct binding of the BRK-BRG1 domain to the zinc finger motifs 4-8 of CTCF, thus suggesting that these domains mediate the interaction of CTCF with the SWI/SNF complex. These findings provide an updated view of the cooperative nature between CTCF and the SWI/SNF ATP-dependent chromatin-remodeling complexes, an important step for understanding how these architectural proteins collaborate to shape the genome.
2021-09-09 | PXD022037 | Pride
Project description:Twist1, a basic helix-loop-helix transcription factor, is expressed in mesenchymal precursor populations during embryogenesis and in metastatic cancer cells. In the developing heart, Twist1 is highly expressed in endocardial cushion (ECC) valve mesenchymal cells and is down regulated during valve differentiation and remodeling. Previous studies demonstrated that Twist1 promotes cell proliferation, migration, and expression of primitive ECM molecules in ECC mesenchymal cells. Furthermore, Twist1 expression is induced in human pediatric and adult diseased heart valves. However, the Twist1 downstream target genes that mediate increased cell proliferation and migration during early heart valve development remain largely unknown. Candidate gene and global gene profiling approaches were used to identify direct transcriptional targets of Twist1 during heart valve development. Candidate target genes were analyzed for evolutionarily conserved regions (ECRs) containing E-box consensus sequences that are potential Twist1 binding sequences. ECRs containing conserved E-box sequences were identified for Twist1 responsive genes Tbx20, Cdh11, Sema3C, Rab39b, and Gadd45a. Twist1 binding to these sequences in vivo was determined by chromatin immunoprecipitation assays, and binding was detected in ECCs but not late stage remodeling valves. In addition identified Twist1 target genes are highly expressed in ECCs and have reduced expression during heart valve remodeling in vivo which is consistent with the expression pattern of Twist1. Together these analyses identify multiple new genes involved in cell proliferation and migration that are differentially expressed in the developing heart valves, are responsive to Twist1 transcriptional function, and contain Twist1 responsive regulatory sequences. Murine MC3T3-E1 preosteoblast cells were treated with siScrambled control or siTwist1 to achieve knockdown of Twist1. Both siScr and siTwist1 were performed in triplicate. Isolated RNA was analyzed with Affymetrix muring MOE 430 2.0 gene chip microarray.
2011-07-27 | E-GEOD-30953 | biostudies-arrayexpress
Project description:The essential process of dosage compensation, which corrects for the imbalance in X-linked gene expression between XX females and XY males, represents a key model for how genes are targeted for coordinated regulation. However, the mechanism by which dosage compensation complexes identify the X-chromosome during early development remained unknown because of the difficulty of sexing embryos prior to zygotic transcription. We used meiotic drive to sex Drosophila embryos prior to zygotic transcription and ChIP-seq to measure dynamics of dosage compensation factor targeting. The Drosophila Male-Specific Lethal dosage compensation complex (MSLc) requires the ubiquitous zinc-finger protein Chromatin-Linked Adaptor for MSL Proteins (CLAMP) to identify the X-chromosome. We observe a multi-stage process in which MSLc first identifies CLAMP binding sites throughout the genome followed by concentration at the strongest X-linked MSLc sites. We provide insight into the dynamic mechanism by which a large transcription complex identifies its binding sites during early development.
2019-12-01 | GSE133637 | GEO
Project description:β-actin is a crucial component of several chromatin remodeling complexes which control chromatin structure and accessibility. The mammalian Brahma-associated factor (BAF) is one such complex that plays essential roles in development and differentiation by regulating the chromatin state of critical genes and opposing the repressive activity of polycomb repressive complexes. While previous work has shown that β-actin loss can lead to extensive changes in gene expression and heterochromatin organization, it is not known if changes in β-actin levels can directly influence chromatin remodeling activities of BAF and polycomb proteins. Here we conduct a comprehensive genomic analysis of β-actin knockout mouse embryonic fibroblasts (MEFs) using ATAC-Seq, HiC-seq, RNA-Seq and ChIP-Seq of various epigenetic marks. We demonstrate that β-actin levels can affect the complex interplay between chromatin remodelers such as BAF/BRG1 and EZH2 in a dosage-dependent manner. Our results show that changes in β-actin levels and associated chromatin remodeling activities can not only impact local chromatin accessibility but also induce reversable changes in 3D genome architecture. Our findings support a novel role for β-actin levels in shaping the chromatin landscape during development and differentiation.
2020-01-01 | GSE133196 | GEO