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Disruption of Multiple Overlapping Functions Following Step-Wise Inactivation of the Extended Myc Network

ABSTRACT: Myc, a member of the Myc Network, supervises proliferation, metabolism and ribosomal function. The Mlx Network cross-talks with the Myc Network and regulates overlapping functions. We describe here the consequences of conditional Myc and/or Mlx gene knockouts (KOs) in primary and immortalized murine embryonic fibroblasts (MEFs). MycKO and MycKOxMlxKO “double KO” (DKO) primary MEFs, but not MlxKO MEFs, rapidly growth-arrested and displayed features of aging and senescence. In DKO MEFs, these were transient, indicating that Mlx was necessary to maintain them. KO MEFs deregulated transcripts pertaining to mitochondrial and ribosomal structure and function, cell cycle, aging, senescence and DNA damage. The expression of DNA damage-related proteins was also abnormal. Immortalized KO MEFs remained proliferation-competent but demonstrated differential sensitivities to genotoxic agents. Immortalized MycKO MEFs spontaneously developed tetraploidy that was Mlx-dependent. Different aspects of MEF aging, senescence and DNA damage responses are therefore differentially regulated by the Myc and Mlx Networks.

ORGANISM(S): Mus musculus

PROVIDER: GSE210362 | GEO | 2023/08/28

REPOSITORIES: GEO

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Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia

Project description:The Myc bHLH-ZIP transcription factor is deregulated by most cancers. As a heterodimer with the bHLH-ZIP protein Max, Myc regulates target genes that contribute to metabolism and proliferation. This “Myc Network” cross-talks with the “Mlx Network” comprised of the Myc-like bHLH-ZIP proteins MondoA and ChREBP and the Max-like bHLH-ZIP protein Mlx. This “Extended Myc Network” regulates genes with both common and distinct functions. We have generated hepatocytes lacking Mlx (mlxKO) or Mlx+Myc (double KO or DKO) and quantified their abilities to replace dying hepatocytes in a murine model of Type I tyosinemia. We find that this function deteriorates as the Extended Myc Network is progressively dismantled. Genes dysregulated in mlxKO and DKO hepatocytes include those involved in translation and mitochondrial function. The Myc and Mlx Networks thus cross-talk with the latter playing a disproportionate role. mycKO and mlxKO mice also develop age-dependent non-alcoholic fatty liver disease and mlxKO and DKO mice develop extensive hepatic adenomatosis not observed in wild-type, mycKO, chrebpKO or mycKOxchrebpKO mice. In addition to demonstrating cooperation between the Myc and Mlx Networks, this study reveals the latter to be more important in maintaining metabolic and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis.

2022-05-05 | GSE181371 | GEO

Expression data from wild-type and Zmpste24-/- mouse embryonic fibroblasts (MEFs) at an early passage (passage 3, P3)

Project description:Zmpste24 is a metalloproteinase processing prelamin A into mature lamin A, a nuclear structure protein. Zmpste24-/- mice which accumulate prelamin A in cells recapitulate accelerated aging phenotypes observed in human premature aging disorder, Hutchinson Gilford progeria sydrome (HGPS). Zmpste24-/- mouse embryonic fibroblasts (MEFs) exhibited genomic instabiliy and accelerated aging at cellular level, which is premature senescence. We performed microarray analysis on Zmpste24-/- MEFs, compared to wild-type littermates' MEFs, at an early passage (P3), which is a pre-symptom stage before cellular senescence occurs in the mutant MEFs, in order to examine gene expression profile and figure out the underneath mechanism triggering the premature aging process. Early passage wild-type and Zmpste24-/- MEFs were collected for RNA extraction, the quality of RNAs were determinded by Electrophoresis Assay (2100 Bioanalyzer, Agilent) and RNA extractions were used for hybridization on Affymetrix microarrays.

2010-11-11 | E-GEOD-25257 | biostudies-arrayexpress

Expression data from wild-type and Zmpste24-/- mouse embryonic fibroblasts (MEFs) at an early passage (passage 3, P3)

2010-11-11 | GSE25257 | GEO

Transcriptional and genomic occupancy profiling from MLX WT and MLX knockout mouse tissues.

Project description:We generated mice null for MAX-like Protein X (MLX), encoded by Mlx. All male mice are sterile. We profiled testes tissue from WT versus KO mice by RNA-Seq. We performed ChIP-Seq on WT and KO testes for MLX and MAX, as well as ChIP-Seq for MLX and MAX from primary B220+ splenic B cells, and ChIP-Seq for MLX, MAX and MNT from 3T3 cell lines derived from WT and KO embryos.

2021-07-31 | GSE165820 | GEO

RNA-seq of H2afj-ko and isogenic WT C57/Bl6-N mouse embryonic fibroblasts in proliferation and after etoposide-induced senescence.

Project description:Determine the effect of knocking out the H2afj gene on the transcriptome of MEFs induced into senescence with etoposide. MEFs were produced from individual H2A.J-ko or isogenic WT C57BL/6-N embryos. 3 different female WT and H2A.J-ko MEFs were used for the transcriptome analyses. MEFs were cultivated in DMEM + Gluta-Max (Gibco 31966) + 10%FBS + pen/strep in a 5% carbon dioxyde and 5% oxygen incubator. MEFs were passed twice before inducing senescence by treatment with 2.5 µM etoposide for 6 days (with media changed after 3 days), followed by 3 days incubation in fresh medium without etoposide.

2020-11-02 | E-MTAB-9704 | biostudies-arrayexpress

Transient DNMT3L expression in mouse embryonic fibroblast (MEFs)

Project description:Global heterochromatin reduction, which is one of the hallmarks of aging cells, is associated with reduced transposable element repression and increased risk of chromatin instability. To ensure genomic integrity, the irreparable cells in a population exit permanently from the cell cycle, and this process is termed “senescence”. However, senescence only blocks the expansion of unwanted cells, and the aberrant chromatin of senescent cells remains unstable. Serendipitously, we found that the transient ectopic expression of a repressive epigenetic modulator, DNA methyltransferase 3-like (DNMT3L) was sufficient to delay the premature senescence progression of late-passage mouse embryonic fibroblasts (MEFs) associated with a tightened global chromatin structure. DNMT3L induces more repressive H3K9 methylation on endogenous retroviruses and downregulates the derepressed transposons in aging MEFs. In addition, we found that a pulse of ectopic DNMT3L resulted in the reestablishment of H3K27me3 on polycomb repressive complex 2 (PRC2)-target genes that were derepressed in old MEFs. We demonstrated that ectopic DNMT3L interacted with PRC2 in MEFs. Our data also suggested that ectopic DNMT3L might guide PRC2 to redress deregulated chromatin regions in aging cells. This study might lead to an epigenetic reinforcement strategy for overcoming aging-associated epimutation and senescence.

2019-08-02 | GSE135258 | GEO

The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

Project description:Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we find that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX, which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin like-growth factor-2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned media from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is conserved in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling.â??The data pproided are histome H4 acetlation data for MLX DN and MLX wt samples; 3 MLX DN H4 Ac Chip seq samples , 3 Inputs, 3 MLX WT H4 Ac samples and 3 WT inputs

2015-11-11 | E-GEOD-74678 | biostudies-arrayexpress

A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism

Project description:To elucidate the effect of senescence in mouse colorectal tumor, the transcriptome of enterocytes from CKI alpha deletion mutants (CKI alpha KO), CKI alpha/p53 double deletion mutants (CKI alpha/p53 DKO) and CKI alpha heterozygous mice (CKI alpha Het) were determined by RNAseq.

2013-06-12 | E-MTAB-1683 | biostudies-arrayexpress

Genomic analysis of mice with endothelium-specific TERT knockout (RNA-Seq)

Project description:Health of endothelial cells (EC) is fundamental for function of vital organs. There is evidence accumulating that senescence of EC is associated with aging-related diseases. However, it has not been established whether EC senescence underlies the pathophysiology of aging. Here, we report a mouse model of EC senescence. Inactivation of telomerase (TERT) expression sets the stage for aging and predisposes cells to replicative senescence. TERT maintains telomere length and has telomere-independent effects on cell transcriptome and physiology. We generated mice with TERT gene knock-out (KO) specifically in EC. We analyzed EC from adipose tissues (AT) and skeletal muscle cells from Tert-EC-KO and control mice raised on either chow or high-calorie diet (HCD) and subjected them to RNA sequencing (RNAseq). Single cell RNAseq data were also obtained for subcutaneous and visceral AT. Preliminary analysis of data deposited online indicates that TERT KO induces premature cell senescence and dysfunction. Moreover, HCD feeding exacerbates the effect of TERT loss. We conclude that the Tert-EC-KO mice are a useful model to study EC senescence and its effects on aging-associated organ dysfunction.

2023-12-05 | GSE239686 | GEO

Mettl3/m6A promotes translation of pathogenic mRNAs to mediate cystogenesis in mouse models of ADPKD

Project description:Purpose: Determine the differential m6A methylation pattern of Mettl3 between wildtype, Pkd1F/RC-KO and Pkd1F/RC-Mettl3-DKO mouse kidneys. Methods: m6A RNA IP using the Magna MeRIP™ m6A Kit (EMD Millipore, catalog #17-10499) was performed on P18 wildtype, Pkd1F/RC-KO and Pkd1F/RC-Mettl3-DKO mouse kidney samples. Two biological replicate samples from each genotype were sequenced. Each sample was a pool of 6 kidneys of the same genotype. The input samples were also sequenced to obtain mRNA profiles. Results: 133 mRNAs were found to be differentially hypermethylated in the Pkd1-KO kidneys compared to the control kidneys and differentially hypomethylated in the Pkd1-Mettl3-DKO kidneys compared to the Pkd1-KO kidneys. Two key pathogenic mRNAs namely, c-Myc and Avpr2 were identified and validated as Mettl3 targets. The mRNA transcript levels were unchanged between Pkd1-KO and Pkd1-Mettl3-DKO kidneys. Conclusion: Mettl3/m6A promotes translation of pathogenic mRNAs to mediate cystogenesis in mouse models of ADPKD.

2021-02-03 | GSE165956 | GEO

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