MAX-mutant small cell lung cancers sustain impaired activities of the MGA-dependent ncPRC1
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ABSTRACT:
PROVIDER: PRJNA603733 | ENA |
REPOSITORIES: ENA
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Project description:The MYC-axis is disrupted in cancer, mostly by activation of the MYC-oncogenes but also through inactivation of the MYC-partner, MAX, or of the MAX-partner, MGA, both also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small cell lung cancer (SCLC) cells and apply genome wide and proteomics analysis to study the tumor suppressor function of MAX. We find that MAX-mutant SCLCs classify as ASCL1-type and lack MYC-transcriptional activities. MAX-restitution triggers pro-differentiation expression profiles that shift when MAX and oncogenic MYC (HMYC/MAX) are co-expressed. Despite the ncPRC1.6 can be formed, the lack of MAX restricts global MGA-occupancy, selectively driving its recruitment towards E2F6-motifs. Conversely, MAX-restitution enhances MGA-occupancy and global gene repression of genes involved in different functionalities, including stem-cell and DNA repair/replication. Collectively, these findings reveal that MAX-mutant SCLCs have ASCL1-characteristics, are MYC-independent and their oncogenic features include a deficient ncPRC1.6-mediated gene repression.
2021-01-18 | GSE144457 | GEO
Project description:The MYC axis is commonly disrupted in cancer, mostly by activation of the MYC family of oncogenes, but also by genetic inactivation of MAX, the obligate partner of MYC, and of the MAX partner, MGA, both of which are members of the polycomb repressive complex, ncPRC1.6. While the oncogenic properties of the MYC family have been extensively studied, the tumor suppressor functions of MAX and MGA and the role of the MYC genes in MAX-mutant cells remain unclear. To address these knowledge gaps, we used chromatin immunoprecipitation, RNA-sequencing and mass spectrometry-based proteomic analysis in MAX-restituted and MYC oncogenic-transformed cell lines derived from human small cell lung cancer (SCLC), which is a high-grade neuroendocrine type of lung cancer. We found that MAX-mutant SCLC cells express ASCL1 and ASCL1-dependent targets, implying that these cells belong to the ASCL1-dependent group of SCLCs. In the absence of MAX, even after ectopic overexpression of MYC, we found no recruitment of MYC to the DNA. Furthermore, MAX reconstitution triggered pro-differentiation expression profiles that shifted when MAX and oncogenic MYC were co-expressed. Although ncPRC1.6 could be formed, the lack of MAX restricted global MGA occupancy, selectively driving its recruitment towards E2F6 motifs. Conversely, MAX restitution enhanced MGA occupancy and global gene repression of genes involved in different functions, including stem-cell and DNA repair/replication. Our data reveal that MAX-mutant SCLCs have ASCL1 characteristics, and are MYC-independent, and that their oncogenic features include deficient ncPRC1.6-mediated gene repression.
2021-09-22 | PXD017658 | Pride
Project description:The transcriptional regulator Mga of Streptococcus pyogenes (the group A streptococcus, GAS) is known to directly activate several virulence genes important for colonization and immune evasion during exponential growth. Transcriptome analysis comparing two mga-1 serotypes (M1 SF370, M6 JRS4) and one mga-2 serotype (M4 GA40634) against their isogenic mga-inactivated strains uncovered a broader Mga regulon profile containing both activated and repressed genes with predicted functions primarily related to the uptake and metabolism of sugars. Although the divergent M1 and M4 Mga profiles were similar in size and content, the M6 JRS4 strain was clearly distinct, even from other M6 strains. Real-time RT-PCR and northern blot analysis validated our microarray results and confirmed that established core Mga regulon genes directly activated by Mga (emm, scpA, sof, fba) exhibited the highest activation levels across all strains tested. A novel ORF (Spy2036) encoding a cytosolic hypothetical protein was highly activated in all three serotypes and was called gene regulated by Mga or grm. Mga was shown to bind directly to Pgrm, which overlaps the Mga-regulated Psof in OF+ strains, suggesting that grm is part of the core Mga regulon and is able to activate two divergently transcribed genes from a single site in a class II background. Both class and serotype specific Mga-regulated genes, such as speB, were apparent. In fact, Mga activated speB as long as it was expressed in the wild type strain, although direct binding of Mga to the PspeB promoter could not be demonstrated. Thus, Mga is able to both directly and indirectly regulate genes shown to be important for virulence and the metabolic homeostasis of GAS. Keywords: Wild-type vs Mga-
2006-08-31 | GSE4598 | GEO
Project description:The transcriptional regulator Mga of Streptococcus pyogenes (the group A streptococcus, GAS) is known to directly activate several virulence genes important for colonization and immune evasion during exponential growth. Transcriptome analysis comparing two mga-1 serotypes (M1 SF370, M6 JRS4) and one mga-2 serotype (M4 GA40634) against their isogenic mga-inactivated strains uncovered a broader Mga regulon profile containing both activated and repressed genes with predicted functions primarily related to the uptake and metabolism of sugars. Although the divergent M1 and M4 Mga profiles were similar in size and content, the M6 JRS4 strain was clearly distinct, even from other M6 strains. Real-time RT-PCR and northern blot analysis validated our microarray results and confirmed that established core Mga regulon genes directly activated by Mga (emm, scpA, sof, fba) exhibited the highest activation levels across all strains tested. A novel ORF (Spy2036) encoding a cytosolic hypothetical protein was highly activated in all three serotypes and was called gene regulated by Mga or grm. Mga was shown to bind directly to Pgrm, which overlaps the Mga-regulated Psof in OF+ strains, suggesting that grm is part of the core Mga regulon and is able to activate two divergently transcribed genes from a single site in a class II background. Both class and serotype specific Mga-regulated genes, such as speB, were apparent. In fact, Mga activated speB as long as it was expressed in the wild type strain, although direct binding of Mga to the PspeB promoter could not be demonstrated. Thus, Mga is able to both directly and indirectly regulate genes shown to be important for virulence and the metabolic homeostasis of GAS. Keywords: Wild-type vs Mga-
2006-08-31 | GSE4597 | GEO
Project description:The transcriptional regulator Mga of Streptococcus pyogenes (the group A streptococcus, GAS) is known to directly activate several virulence genes important for colonization and immune evasion during exponential growth. Transcriptome analysis comparing two mga-1 serotypes (M1 SF370, M6 JRS4) and one mga-2 serotype (M4 GA40634) against their isogenic mga-inactivated strains uncovered a broader Mga regulon profile containing both activated and repressed genes with predicted functions primarily related to the uptake and metabolism of sugars. Although the divergent M1 and M4 Mga profiles were similar in size and content, the M6 JRS4 strain was clearly distinct, even from other M6 strains. Real-time RT-PCR and northern blot analysis validated our microarray results and confirmed that established core Mga regulon genes directly activated by Mga (emm, scpA, sof, fba) exhibited the highest activation levels across all strains tested. A novel ORF (Spy2036) encoding a cytosolic hypothetical protein was highly activated in all three serotypes and was called gene regulated by Mga or grm. Mga was shown to bind directly to Pgrm, which overlaps the Mga-regulated Psof in OF+ strains, suggesting that grm is part of the core Mga regulon and is able to activate two divergently transcribed genes from a single site in a class II background. Both class and serotype specific Mga-regulated genes, such as speB, were apparent. In fact, Mga activated speB as long as it was expressed in the wild type strain, although direct binding of Mga to the PspeB promoter could not be demonstrated. Thus, Mga is able to both directly and indirectly regulate genes shown to be important for virulence and the metabolic homeostasis of GAS. Keywords: Wild-type vs Mga-
2006-08-31 | GSE4596 | GEO
Project description:We sought understand the molecular mehcanism of gene regulation by Mga and its contribution to GAS pathogenesis in serotype M59 GAS through whole transcriptome analysis of strains with phosphorylation mimicking substitutions in key histidine residues of Mga. There were 6 strains analyzed, each in triplicate replicates: 1)wild-type GAS, 2)mga deletion strain 3)mga with alanine at H207 4)mga with aspartate at H207, 5) mga with alanine at H273 6)mga with aspartate at H273
2015-04-18 | E-GEOD-67988 | biostudies-arrayexpress
Project description:JRS4 is our wild-type M6 serotype GAS and JRS519 is our Mga- M6 serotype GAS. SF370 is our wild-type M1 serotype GAS and KSM165L is our Mga- M1 serotype GAS. Table 1: Genomic Normalization Description: Step by Step instructions for the removal of outlier background data and any ORF data that did not meet threshold of 2SD above background average, using original data from gpr file provided in each of the sample files. Table 2: M1 Mga+ vs Mga- Description: Step by Step instructions for the removal of outlier data as compared across all possible data points for each ORF. Data points after genomic normalization are used with resultant averages and standard deviations for each ORF computed. Table 3: M6 Mga+ vs Mga- Description: Step by Step instructions for the removal of outlier data as compared across all possible data points for each ORF. Data points after genomic normalization are used with resultant averages and standard deviations for each ORF computed. Keywords: repeat sample
2005-04-06 | GSE1895 | GEO
Project description:Using RNA-seq to identify genes that regulated by MGA and MYC
2020-01-18 | GSE112190 | GEO
Project description:MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with RUNX1::RUNX1T1, however, very little is known about the impact of these MGA alterations on normal hematopoiesis or disease progression. We show that representative MGA mutations identified in patient samples abolish protein-protein interactions and transcriptional activity. Using a series of human and mouse model systems, including a newly developed conditional knock-out mouse strain, we demonstrate that loss of MGA results in upregulation of MYC and E2F targets, cell cycle genes, mTOR signaling, and oxidative phosphorylation in normal hematopoietic cells, leading to enhanced proliferation. The loss of MGA induces an open chromatin state at promotors of genes involved in cell cycle and proliferation. RUNX1::RUNX1T1 expression in Mga-deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1T1 fusion oncoprotein to enhance leukemogenesis.
2024-05-15 | GSE253752 | GEO