The MYCL and MXD1 transcription factors regulate the fitness of murine dendritic cells
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PROVIDER: PRJNA593609 | ENA |
REPOSITORIES: ENA
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Project description:The present study reveals LMYC and MXD1 as novel regulators of a transcriptional program that is modulated during the maturation of Batf3-dependent dendritic cells (also known as type I classical dendritic cells or cDC1s). We used microarray analysis with ERCC spike in controls to determine the transcriptional effects of MYCL and MXD1 deficiency at steady state and after activation with poly IC. Mycl-deficient mice are available from Jackson laboratories as B6.129S6(C)-Mycltm1.1Kmm/J. Mxd1-/- mice were provided by R. Eisenman.
2019-12-05 | GSE141492 | GEO
Project description:We previously found that MYCL is required by a Batf3-dependent classical dendritic cell subset (cDC1) for optimal CD8 T cell priming, but the underlying mechanism has remained unclear. The MAX-binding proteins encompass a family of transcription factors with overlapping DNA-binding specificities, conferred by a C-terminal basic helix-loop-helix domain, which mediates heterodimerization. Thus, regulation of transcription by these factors is dependent on divergent N-terminal domains. The MYC family, including MYCL, has actions that are reciprocal to the MXD family, which is mediated through the recruitment of higher-order activator and repressor complexes, respectively. As potent proto-oncogenes, models of MYC family function have been largely derived from their activity at supraphysiological levels in tumor cell lines. MYC and MYCN have been studied extensively, but empirical analysis of MYCL function had been limited due to highly restricted, lineage-specific expression in vivo. Here we observed that Mycl is expressed in immature cDC1s but repressed on maturation, concomitant with Mxd1 induction in mature cDC1s. We hypothesized that MYCL and MXD1 regulate a shared, but reciprocal, transcriptional program during cDC1 maturation. In agreement, immature cDC1s in Mycl -/- -deficient mice exhibited reduced expression of genes that regulate core biosynthetic processes. Mature cDC1s from Mxd1 -/- mice exhibited impaired ability to inhibit the transcriptional signature otherwise supported by MYCL. The present study reveals LMYC and MXD1 as regulators of a transcriptional program that is modulated during the maturation of Batf3-dependent cDC1s.
| S-EPMC7060746 | biostudies-literature
Project description:β cell proliferation rates decline with age and adult β cells have limited self-duplicating activity for regeneration, which predisposes to diabetes. Here we show that, among MYC family members, Mycl was expressed preferentially in proliferating immature endocrine cells. Genetic ablation of Mycl caused a modest reduction in cell proliferation of pancreatic endocrine cells in neonatal mice. By contrast, systemic expression of Mycl in mice stimulated proliferation in pancreatic islet cells and resulted in expansion of pancreatic islets without forming tumors in other organs. Single-cell RNA sequencing and genetic tracing experiments revealed that the expression of Mycl provoked transcription signatures associated with immature proliferating endocrine cells and stimulated self-duplication in adult hormone-expressing cells. The expanded hormone-expressing cells ceased proliferation but persisted after withdrawal of Mycl expression. Remarkably, a subset of the expanded α cells gave rise to insulin-producing cells after the withdrawal. Moreover, transient Mycl expression in vivo was sufficient to normalize increased blood glucose levels in diabetic mice evoked by chemical ablation of β cells. In vitro expression of Mycl similarly provoked active replication without inducing apoptosis in adult hormone-expressing islet cells, even those from aged mice. Furthermore, the expanded islet cells functioned in diabetic mice after transplantation. Finally, we show that MYCL stimulated self-duplication of human adult cadaveric islet cells. Collectively, these results demonstrate that sole induction of Mycl expands adult β cells both in vivo and in vitro. Moreover, islet cell-specific reprogramming via transient Mycl transduction elicits endogenous expansion of insulin-producing cells in adult pancreas through both self-duplication of β cells and transdifferentiation ofα cells into insulin-producing cells, which may provide a regenerative strategy of β cells.
2022-01-29 | GSE163947 | GEO
Project description:β cell proliferation rates decline with age and adult β cells have limited self-duplicating activity for regeneration, which predisposes to diabetes. Here we show that, among MYC family members, Mycl was expressed preferentially in proliferating immature endocrine cells. Genetic ablation of Mycl caused a modest reduction in cell proliferation of pancreatic endocrine cells in neonatal mice. By contrast, systemic expression of Mycl in mice stimulated proliferation in pancreatic islet cells and resulted in expansion of pancreatic islets without forming tumors in other organs. Single-cell RNA sequencing and genetic tracing experiments revealed that the expression of Mycl provoked transcription signatures associated with immature proliferating endocrine cells and stimulated self-duplication in adult hormone-expressing cells. The expanded hormone-expressing cells ceased proliferation but persisted after withdrawal of Mycl expression. Remarkably, a subset of the expanded α cells gave rise to insulin-producing cells after the withdrawal. Moreover, transient Mycl expression in vivo was sufficient to normalize increased blood glucose levels in diabetic mice evoked by chemical ablation of β cells. In vitro expression of Mycl similarly provoked active replication without inducing apoptosis in adult hormone-expressing islet cells, even those from aged mice. Furthermore, the expanded islet cells functioned in diabetic mice after transplantation. Finally, we show that MYCL stimulated self-duplication of human adult cadaveric islet cells. Collectively, these results demonstrate that sole induction of Mycl expands adult β cells both in vivo and in vitro. Moreover, islet cell-specific reprogramming via transient Mycl transduction elicits endogenous expansion of insulin-producing cells in adult pancreas through both self-duplication of β cells and transdifferentiation ofα cells into insulin-producing cells, which may provide a regenerative strategy of β cells.
2022-01-29 | GSE178726 | GEO
Project description:Tissue function depends on the relative proportions of multiple cell types. In the airway, basal stem cells differentiate into both multiciliated and secretory cells, which together protect the lungs from inhaled pathogens and particulates. To define how airway stem cells differentiate, we mapped differentiation trajectories using single-cell mRNA sequencing (scRNA-seq) and identified a transitional intermediate cell state in between basal stem cells and differentiated cells. These intermediate cells induce different gene expression programs that precede differentiation into either multiciliated or secretory cells. For example, we found that within the intermediate cell population, multiciliated cell precursors express Mycl, encoding a MYC-family transcription factor, and secretory cell precursors express Hey1, encoding a transcriptional repressor. We also found that Notch signaling acts on intermediate cells to repress Mycl and induce Hey1. We further show MYCL expression is sufficient to drive multiciliated cell fate, whereas HEY1 expression is sufficient to repress multiciliated cell fate. Using CUT&RUN, we made the surprising observation that MYCL and HEY1 bind to many of the same regulatory elements near genes encoding early regulators of multiciliated cell differentiation. We conclude that intermediate cells receiving Notch signals induce HEY1 to repress the multiciliated cell fate and become secretory cells, while intermediate cells not receiving Notch signals induce MYCL to promote the multiciliated cell fate. These experiments reveal that during airway stem cell differentiation Notch signaling balances the production of two different cell types by regulating the functions of two opposing transcription factors, MYCL and HEY1.
2025-12-31 | GSE215057 | GEO
Project description:To determine if MYCL or EP400 knockdown would affect Max target genes in Merkel cell carcinoma cell line MKL-1, we performed RNA-seq analyses of MKL-1 cells inducibly expressing shMYCL and two different EP400 shRNA -2, -3 and compared to ChIP-seq data using BETA analyses.
2017-09-28 | GSE100183 | GEO
Project description:In cells derived from a genetically engineered Rb1 and Trp53 loss mouse model of SCLC (RP) expression of one of the three MYC family members induced from the endogenous locus using CRISPR activation. Cells were first stably transfected with the lenti-MS2-p65-HSF1 activator plasmid. Respective sgRNAs targeting either Myc, Mycl or MYCN were then cloned into the lentiSAMv2 system and transfected separately into the MS2-p65-HSF1 cells using lentiviral delivery.
2019-07-09 | E-MTAB-7411 | biostudies-arrayexpress
Project description:Opposing transcription factors MYCL and HEY1 mediate the Notch-dependent airway stem cell fate decision
| PRJNA888348 | ENA
Project description:Engineered probiotics limit T-cell driven CNS autoimmunity by promoting mitochondrial fitness in dendritic cells
| PRJNA779082 | ENA
Project description:During steady-state cell growth, individual enzymatic fluxes can be directly inferred from growth rate by mass conservation, but the inverse problem remains unsolved. Perturbing the flux and expression of a single enzyme could have pleiotropic effects that may or may not dominate the impact on cell fitness. Here, we quantitatively dissect the molecular and global responses to varied expression of translation termination factors (peptide release factors, RFs) in the bacterium Bacillus subtilis. While endogenous RF expression maximizes proliferation, deviations in expression lead to unexpected distal regulatory responses that dictate fitness reduction. Molecularly, RF depletion causes expression imbalance at specific operons, which activates master regulators and detrimentally overrides the transcriptome. Through these spurious connections, RF abundances are thus entrenched by focal points within the regulatory network, in one case located at a single stop codon. Such regulatory entrenchment suggests that predictive bottom-up models of expression-fitness landscapes will require near-exhaustive characterization
2020-11-28 | GSE162169 | GEO