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Project description:Many tumors of endodermal origin are composed of highly secretory cancer cells that must adapt endoplasmic reticulum (ER) activity to enable proper folding of secretory proteins, prevent ER stress and thus maintain their viability. In pancreatic ductal adenocarcinoma (PDAC), well-differentiated and secretory cancer cells coexist with poorly differentiated cells with quasi-mesenchymal features. We found that the differentiated PDAC cells, but not the undifferentiated ones, expressed an ER membrane-associated transcription factor (TF), Myelin Regulatory Factor (MYRF), that is released by self-cleavage and translocates to the nucleus. MYRF expression was directly controlled by HNF1B, a TF maintaining epithelial identity in PDAC, and it acted to fine-tune the expression of genes encoding highly glycosylated and cysteine-rich secretory proteins, thus preventing ER overload. MYRF-deficient PDAC cells showed anatomical and biochemical signs of ER stress, impaired proliferation and inability to form spheroids in vitro, while in vivo they generated highly secretory but poorly proliferating and hypo-cellular tumors. These data indicate a role of MYRF in the control of homeostasis and proliferation of cancer cells with high secretory activity
2020-09-18 | GSE145628 | GEO
Project description:Many tumors of endodermal origin are composed of highly secretory cancer cells that must adapt endoplasmic reticulum (ER) activity to enable proper folding of secretory proteins, prevent ER stress and thus maintain their viability. In pancreatic ductal adenocarcinoma (PDAC), well-differentiated and secretory cancer cells coexist with poorly differentiated cells with quasi-mesenchymal features. We found that the differentiated PDAC cells, but not the undifferentiated ones, expressed an ER membrane-associated transcription factor (TF), Myelin Regulatory Factor (MYRF), that is released by self-cleavage and translocates to the nucleus. MYRF expression was directly controlled by HNF1B, a TF maintaining epithelial identity in PDAC, and it acted to fine-tune the expression of genes encoding highly glycosylated and cysteine-rich secretory proteins, thus preventing ER overload. MYRF-deficient PDAC cells showed anatomical and biochemical signs of ER stress, impaired proliferation and inability to form spheroids in vitro, while in vivo they generated highly secretory but poorly proliferating and hypo-cellular tumors. These data indicate a role of MYRF in the control of homeostasis and proliferation of cancer cells with high secretory activity
2020-09-18 | GSE145627 | GEO
Project description:Pancreatic cancer cells require the transcription factor MYRF (Myelin Regulatory Factor) to maintain ER homeostasis
| PRJNA607766 | ENA
Project description:Pancreatic cancer cells require the transcription factor MYRF (Myelin Regulatory Factor) to maintain ER homeostasis (ChIP-Seq).
| PRJNA607770 | ENA
Project description:Pancreatic cancer cells require the transcription factor MYRF (Myelin Regulatory Factor) to maintain ER homeostasis (RNA-Seq).
| PRJNA607769 | ENA
Project description:Myelination of the central nervous system (CNS) is critical to vertebrate nervous systems for efficient neural signaling. CNS myelination occurs as oligodendrocytes terminally differentiate, a process regulated in part by the myelin regulatory factor, MYRF. Using bioinformatics and extensive biochemical and functional assays, we find that MYRF is generated as an integral membrane protein that must be processed to release its transcription factor domain from the membrane. In contrast to most membrane-bound transcription factors, MYRF proteolysis seems constitutive and independent of cell- and tissue-type, as we demonstrate by reconstitution in E. coli and yeast. The apparent absence of physiological cues raises the question as to how and why MYRF is processed. By using computational methods capable of recognizing extremely divergent sequence homology, we identified a MYRF protein domain distantly related to bacteriophage tailspike proteins. Although occurring in otherwise unrelated proteins, the phage domains are known to chaperone the tailspike proteins' trimerization and auto-cleavage, raising the hypothesis that the MYRF domain might contribute to a novel activation method for a membrane-bound transcription factor. We find that the MYRF domain indeed serves as an intramolecular chaperone that facilitates MYRF trimerization and proteolysis. Functional assays confirm that the chaperone domain-mediated auto-proteolysis is essential both for MYRF's transcriptional activity and its ability to promote oligodendrocyte maturation. This work thus reveals a previously unknown key step in CNS myelination. These data also reconcile conflicting observations of this protein family, different members of which have been identified as transmembrane or nuclear proteins. Finally, our data illustrate a remarkable evolutionary repurposing between bacteriophages and eukaryotes, with a chaperone domain capable of catalyzing trimerization-dependent auto-proteolysis in two entirely distinct protein and cellular contexts, in one case participating in bacteriophage tailspike maturation and in the other activating a key transcription factor for CNS myelination.
| S-EPMC3742443 | biostudies-literature
Project description:The myelination of axons is a crucial step during vertebrate central nervous system (CNS) development, allowing for rapid and energy efficient saltatory conduction of nerve impulses. Accordingly, the differentiation of oligodendrocytes, the myelinating cells of the CNS, and their expression of myelin genes are under tight transcriptional control. We previously identified a putative transcription factor, Myelin Regulatory Factor (Myrf), as being vital for CNS myelination. Myrf is required for the generation of CNS myelination during development and also for its maintenance in the adult. It has been controversial, however, whether Myrf directly regulates transcription, with reports of a transmembrane domain and lack of nuclear localization. Here we show that Myrf is a membrane-associated transcription factor that undergoes an activating proteolytic cleavage to separate its transmembrane domain-containing C-terminal region from a nuclear-targeted N-terminal region. Unexpectedly, this cleavage event occurs via a protein domain related to the autoproteolytic intramolecular chaperone domain of the bacteriophage tail spike proteins, the first time this domain has been found to play a role in eukaryotic proteins. Using ChIP-Seq we show that the N-terminal cleavage product directly binds the enhancer regions of oligodendrocyte-specific and myelin genes. This binding occurs via a defined DNA-binding consensus sequence and strongly promotes the expression of target genes. These findings identify Myrf as a novel example of a membrane-associated transcription factor and provide a direct molecular mechanism for its regulation of oligodendrocyte differentiation and CNS myelination.
| S-EPMC3742440 | biostudies-literature
Project description:Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis. Gross neurologic functioning appears to be within normal limits. In both individuals a de novo variant in MYRF was identified using exome sequencing. Neither variant is found in gnomAD. Heterozygous variants in MYRF should be considered in patients with variants of Scimitar syndrome and urogenital anomalies.
| S-EPMC5867271 | biostudies-literature
Project description:Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.
| S-EPMC6527243 | biostudies-literature
Project description:Perineuronal nets (PNNs) are densely packed extracellular matrices that cover the cell body of fast-spiking inhibitory neurons. PNNs stabilize synapses inhibiting synaptic plasticity. Here we show that synaptic terminals of fast-spiking interneurons localize to holes in the PNNs in the adult mouse somatosensory cortex. Approximately 95% of holes in the PNNs contain synapses and astrocytic processes expressing Kir4.1, glutamate and GABA transporters. Hence, holes in the PNNs contain tripartite synapses. In the adult mouse brain, PNN degradation causes an expanded astrocytic coverage of the neuronal somata without altering the axon terminals. The loss of PNNs impairs astrocytic transmitter and potassium uptake, resulting in the spillage of glutamate into the extrasynaptic space. Our data show that PNNs and astrocytes cooperate to contain synaptically released signals in physiological conditions. Their combined action is altered in mouse models of Alzheimer's disease and epilepsy where PNNs are disrupted.
| S-EPMC11303255 | biostudies-literature