Gtf2i-encoded transcription factor Tfii-i regulates myelination via Sox10 and Mbp regulatory elements
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ABSTRACT:
PROVIDER: PRJNA1204338 | ENA |
REPOSITORIES: ENA
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Project description:The transcriptional regulatory network governing the differentiation and functionality of oligodendrocytes is essential for the formation and maintenance of the myelin sheath, and hence for the proper function of the nervous system. Perturbations in the intricate interplay of transcriptional effectors within this network can lead to a variety of nervous system pathologies. In this study, we have identified Gtf2i-encoded general transcription factor II-I (Tfii-i), as a regulator of key myelination-related genes. Gtf2i deletion from myelinating glia cells in mice led to functional alterations in CNS myelin, including elevated mRNA and protein expression levels of the central myelin component Mbp, enhanced connectivity properties, and thicker myelin wrapping axons with increased diameters. These changes resulted in faster axonal conduction across the corpus callosum, and improved motor coordination. In the PNS, Gtf2i deletion from Schwann cells led to hypermyelination of the tibial branch of the sciatic nerve. Furthermore, we show that, in myelinating oligodendrocytes, Tfii-i directly binds to regulatory elements of Sox10 and Mbp. These findings add to our understanding of myelination regulation and specifically elucidate a cell-autonomous mechanism for Tfii-i in myelinating glia transcriptional network.
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Project description:The transcriptional regulatory network governing the differentiation and functionality of oligodendrocytes is essential for the formation and maintenance of the myelin sheath, and hence for the proper function of the nervous system. Perturbations in the intricate interplay of transcriptional effectors within this network can lead to a variety of nervous system pathologies. In this study, we have identified Gtf2i-encoded general transcription factor II-I (Tfii-i) as a regulator of key myelination-related genes. To assess how Tfii-i absence from oligodendrocytes alters myelin properties on a molecular level, we compared the biochemically-enriched myelin fraction purified from brains of Gtf2i-KO and control mice by label-free quantitative mass spectrometry using the MSE-type data-independent acquisition (DIA) mode. We found an increased protein abundance of several key myelin proteins such as Mbp and Mog, while the abundance of Gpr37 was decreased, overall indicating a molecular hypermyelination phenotype in the absence of Tfii-i. These results, together with findings from - among others - structural, electrophysiological and behavioral approaches, show that Gtf2i deletion from myelinating glia cells in mice led to functional alterations in CNS myelin, which resulted in faster axonal conduction and improved motor coordination.
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Project description:The molecular mechanisms underlying the pathogenesis of TETs are poorly understood. Recently we reported a common missense mutation on GTF2I gene in thymic tumors and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of thymic epithelial cells and up-regulated several oncogenic genes. Using CRISPR/Cas9n, Gtf2i T1211A knock-in cells exhibited distinct features of cancerous cells including cell transformation, aneuploidy, tumor growth in xenograft, and survival after DNA damage or glucose deprivation. We also observed that Gtf2i mutation increased the expression of several glycolytic enzymes, cyclooxygenase-2, and altered lipid metabolism. Elevated COX-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver mutation that is responsible for transformation of thymic epithelial cells.
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Project description:The molecular mechanisms underlying the pathogenesis of TETs are poorly understood. Recently we reported a common missense mutation on GTF2I gene in thymic tumors and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of thymic epithelial cells and up-regulated several oncogenic genes. Using CRISPR/Cas9n, Gtf2i T1211A knock-in cells exhibited distinct features of cancerous cells including cell transformation, aneuploidy, tumor growth in xenograft, and survival after DNA damage or glucose deprivation. We also observed that Gtf2i mutation increased the expression of several glycolytic enzymes, cyclooxygenase-2, and altered lipid metabolism. Elevated COX-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver mutation that is responsible for transformation of thymic epithelial cells.
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Project description:We expressed biotin-tagged transcription factor TFII-I (GTF2I) in K562 cells and subjected crosslinked chromatin to streptavidin mediated pull down. We subjected the isolated DNA to Illumina sequencing. We identified 18920 TFII-I binding peaks. Nearest gene analysis revealed 5886 genes associated with a TFII-I binding peak in proliferating K562 cells. We generated two K562 single cell clones stably expressing bio-tagged TFII-I, and K562 cells expressing only the BirA protein biotin ligase from E.coli. These three clones were subjected to streptavidin mediated pull down and Illumina sequencing.
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