scholarly journals Insulin Signaling-independent Activation of DAF-16 Shapes the Transcriptome during Normal Aging

2018 ◽  
Author(s):  
Shang-Tong Li ◽  
Han-Qing Zhao ◽  
Pan Zhang ◽  
Chung-Yi Liang ◽  
Yan-Ping Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Signaling ◽  
Aging Process ◽  
Normal Aging ◽  
Regulatory Mechanisms ◽  
Regulation Of Transcription ◽  
Wild Type ◽  
Age Dependent ◽  
Expression Program

SummaryThe roles and regulatory mechanisms of transriptome changes during aging are unclear. It has been proposed that the transcriptome suffers decay during aging owing to age-associated down-regulation of transcription factors. In this study, we characterized the role of a transcription factor DAF-16, which is a highly conserved lifespan regulator, in the normal aging process of Caenorhabditis elegans. We found that DAF-16 translocates into the nucleus in aged wild-type worms and activates the expression of hundreds of genes in response to age-associated cellular stress. Most of the age-dependent DAF-16 targets are different from the canonical DAF-16 targets downstream of insulin signaling, indicating that activation of DAF-16 during aging is not due to reduced insulin signaling from DAF-2. Further analysis showed that it is due to the loss of proteostasis during aging, at least in part. We also found that without daf-16, dramatic gene expression changes occur as early as on adult day 2, indicating that DAF-16 acts to stabilize the transcriptome during normal aging. Our results thus reveal that normal aging is not simply a process in which the gene expression program descends into chaos due to loss of regulatory activities; rather, there is active transcriptional regulation that fights aging.

scholarly journals The nucleoplasmic interactions among Lamin A/C-pRB-LAP2α-E2F1 are modulated by dexamethasone

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anastasia Ricci ◽  
Sara Orazi ◽  
Federica Biancucci ◽  
Mauro Magnani ◽  
Michele Menotta
Keyword(s):  
Gene Expression ◽  
Cell Cycle Progression ◽  
Regulation Of Gene Expression ◽  
Lamin A ◽  
Wild Type ◽  
Cycle Progression ◽  
C Dynamics ◽  
E2f Transcription Factor ◽  
Transcription Factor 1

AbstractAtaxia telangiectasia (AT) is a rare genetic neurodegenerative disease. To date, there is no available cure for the illness, but the use of glucocorticoids has been shown to alleviate the neurological symptoms associated with AT. While studying the effects of dexamethasone (dex) in AT fibroblasts, by chance we observed that the nucleoplasmic Lamin A/C was affected by the drug. In addition to the structural roles of A-type lamins, Lamin A/C has been shown to play a role in the regulation of gene expression and cell cycle progression, and alterations in the LMNA gene is cause of human diseases called laminopathies. Dex was found to improve the nucleoplasmic accumulation of soluble Lamin A/C and was capable of managing the large chromatin Lamin A/C scaffolds contained complex, thus regulating epigenetics in treated cells. In addition, dex modified the interactions of Lamin A/C with its direct partners lamin associated polypeptide (LAP) 2a, Retinoblastoma 1 (pRB) and E2F Transcription Factor 1 (E2F1), regulating local gene expression dependent on E2F1. These effects were differentially observed in both AT and wild type (WT) cells. To our knowledge, this is the first reported evidence of the role of dex in Lamin A/C dynamics in AT cells, and may represent a new area of research regarding the effects of glucocorticoids on AT. Moreover, future investigations could also be extended to healthy subjects or to other pathologies such as laminopathies since glucocorticoids may have other important effects in these contexts as well.

Retrovirus-induced interference with collagen I gene expression in Mov13 fibroblasts is maintained in the absence of DNA methylation

1991 ◽  
Vol 11 (1) ◽  
pp. 47-54
Author(s):  
H Chan ◽  
S Hartung ◽  
M Breindl
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Chromatin Structure ◽  
Transcriptional Activity ◽  
Xenopus Laevis Oocytes ◽  
Regulatory Sequences ◽  
Type I ◽  
Wild Type ◽  
Col1a1 Gene

We have studied the role of DNA methylation in repression of the murine alpha 1 type I collagen (COL1A1) gene in Mov13 fibroblasts. In Mov13 mice, a retroviral provirus has inserted into the first intron of the COL1A1 gene and blocks its expression at the level of transcriptional initiation. We found that regulatory sequences in the COL1A1 promoter region that are involved in the tissue-specific regulation of the gene are unmethylated in collagen-expressing wild-type fibroblasts and methylated in Mov13 fibroblasts, confirming and extending earlier observations. To directly assess the role of DNA methylation in the repression of COL1A1 gene transcription, we treated Mov13 fibroblasts with the demethylating agent 5-azacytidine. This treatment resulted in a demethylation of the COL1A1 regulatory sequences but failed to activate transcription of the COL1A1 gene. Moreover, the 5-azacytidine treatment induced a transcription-competent chromatin structure in the retroviral sequences but not in the COL1A1 promoter. In DNA transfection and microinjection experiments, we found that the provirus interfered with transcriptional activity of the COL1A1 promoter in Mov13 fibroblasts but not in Xenopus laevis oocytes. In contrast, the wild-type COL1A1 promoter was transcriptionally active in Mov13 fibroblasts. These experiments showed that the COL1A1 promoter is potentially transcriptionally active in the presence of proviral sequences and that Mov13 fibroblasts contain the trans-acting factors required for efficient COL1A1 gene expression. Our results indicate that the provirus insertion in Mov13 can inactivate COL1A1 gene expression at several levels. It prevents the developmentally regulated establishment of a transcription-competent methylation pattern and chromatin structure of the COL1A1 domain and, in the absence of DNA methylation, appears to suppress the COL1A1 promoter in a cell-specific manner, presumably by assuming a dominant chromatin structure that may be incompatible with transcriptional activity of flanking cellular sequences.

scholarly journals Role of Sigma Factors in Controlling Global Gene Expression in Light/Dark Transitions in the Cyanobacterium Synechocystis sp. Strain PCC 6803

2007 ◽  
Vol 189 (21) ◽  
pp. 7829-7840 ◽  
Author(s):  
Tina C. Summerfield ◽  
Louis A. Sherman
Keyword(s):  
Gene Expression ◽  
Global Gene Expression ◽  
Growth Conditions ◽  
Day Length ◽  
Regulation Of Transcription ◽  
Wild Type ◽  
Protein Levels ◽  
In The Wild ◽  
Altered Gene ◽  
Pcc 6803

ABSTRACT We report on differential gene expression in the cyanobacterium Synechocystis sp. strain PCC 6803 after light-dark transitions in wild-type, ΔsigB, and ΔsigD strains. We also studied the effect of day length in the presence of glucose on a ΔsigB ΔsigE mutant. Our results indicated that the absence of SigB or SigD predominately altered gene expression in the dark or in the light, respectively. In the light, approximately 350 genes displayed transcript levels in the ΔsigD strain that were different from those of the wild type, with over 200 of these up-regulated in the mutant. In the dark, removal of SigB altered more than 150 genes, and the levels of 136 of these were increased in the mutant compared to those in the wild type. The removal of both SigB and SigE had a major impact on gene expression under mixotrophic growth conditions and resulted in the inability of cells to grow in the presence of glucose with 8-h light and 16-h dark cycles. Our results indicated the importance of group II σ factors in the global regulation of transcription in this organism and are best explained by using the σ cycle paradigm with the stochastic release model described previously (R. A. Mooney, S. A. Darst, and R. Landick, Mol. Cell 20:335-345, 2005). We combined our results with the total protein levels of the σ factors in the light and dark as calculated previously (S. Imamura, S. Yoshihara, S. Nakano, N. Shiozaki, A. Yamada, K. Tanaka, H. Takahashi, M. Asayama, and M. Shirai, J. Mol. Biol. 325:857-872, 2003; S. Imamura, M. Asayama, H. Takahashi, K. Tanaka, H. Takahashi, and M. Shirai, FEBS Lett. 554:357-362, 2003). Thus, we concluded that the control of global transcription is based on the amount of the various σ factors present and able to bind RNA polymerase.

Time- and age-dependent effects of serotonin on gasping and autoresuscitation in neonatal mice

2013 ◽  
Vol 114 (12) ◽  
pp. 1668-1676 ◽  
Author(s):  
Jianping Chen ◽  
Jennifer Magnusson ◽  
Gerard Karsenty ◽  
Kevin J. Cummings
Keyword(s):  
Heart Rate ◽  
Tryptophan Hydroxylase ◽  
Single Injection ◽  
Heart Rate Recovery ◽  
Wild Type ◽  
Tryptophan Hydroxylase 2 ◽  
Age Dependent ◽  
Long Time ◽  
Time Required

The role of brain stem serotonin (5-hydroxytryptamine, 5-HT) in autoresuscitation in neonatal life is unclear. We hypothesized that a specific loss of 5-HT would compromise gasping and autoresuscitation mainly in the second postnatal week and that acute restoration of 5-HT would reverse the defects. We exposed postnatal day (P)4–5, P8–9, and P11–12 tryptophan-hydroxylase-2 knockout ( TPH2−/−) and wild-type littermates (WT) to 10 episodes of anoxia (97% N2, 3% CO2), measuring survival, gasp latency, gasp frequency ( fB), and the time required to restore eupnea and heart rate. We also tested P8–9 TPH2−/− mice after restoring 5-HT with a single injection of 5-hydroxytryptophan (5-HTP) 1–2 h before testing or with multiple injections beginning 24 h before testing. At P4–5 and P8–9, but not at P11–12, gasp latency and the recovery of eupnea were delayed ∼2- to 3-fold in TPH2−/− pups compared with WT ( P < 0.001). At all ages, TPH2−/− pups displayed reduced gasp fB (∼20–30%; P < 0.001) and delayed heart rate recovery (∼60%; P = 0.002) compared with WT littermates. TPH2−/− survival was reduced compared with WT ( P < 0.001), especially at P8–9 and P11–12 ( P = 0.004). Whereas 1–2 h of 5-HTP treatment improved the gasp latency and fB of P8–9 TPH2−/− pups, improved cardiorespiratory recovery and survival required 24 h of treatment. Our data suggest that 5-HT operates over a long time span (∼24 h) to improve survival during episodic severe hypoxia. Early in development (P4–9), 5-HT is critical for both respiratory and cardiovascular components of autoresuscitation; later (P11–12), it is critical mainly for cardiovascular components. Nevertheless, the effect of 5-HT deficiency on survival is most striking from P8 to P12.

Role of the Hypoxia-Inducible Factor Pathway in Normal and Osteoarthritic Meniscus and in Mice after Destabilization of the Medial Meniscus

Cartilage ◽  
2020 ◽  
pp. 194760352095814
Author(s):  
Austin V. Stone ◽  
Richard F. Loeser ◽  
Michael F. Callahan ◽  
Margaret A. McNulty ◽  
David L. Long ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Medial Meniscus ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Early Time ◽  
Wild Type ◽  
Inflammatory Stimuli ◽  
Hif Pathway

Objective Meniscus injury and the hypoxia-inducible factor (HIF) pathway are independently linked to osteoarthritis pathogenesis, but the role of the meniscus HIF pathway remains unclear. We sought to identify and evaluate HIF pathway response in normal and osteoarthritic meniscus and to examine the effects of Epas1 (HIF-2α) insufficiency in mice on early osteoarthritis development. Methods Normal and osteoarthritic human meniscus specimens were obtained and used for immunohistochemical evaluation and cell culture studies for the HIF pathway. Meniscus cells were treated with pro-inflammatory stimuli, including interleukins (IL)-1β, IL-6, transforming growth factor (TGF)-α, and fibronectin fragments (FnF). Target genes were also evaluated with HIF-1α and HIF-2α (Epas1) overexpression and knockdown. Wild-type ( n = 36) and Epas1+/− ( n = 30) heterozygous mice underwent destabilization of the medial meniscus (DMM) surgery and were evaluated at 2 and 4 weeks postoperatively for osteoarthritis development using histology. Results HIF-1α and HIF-2α immunostaining and gene expression did not differ between normal and osteoarthritic meniscus. While pro-inflammatory stimulation significantly increased both catabolic and anabolic gene expression in the meniscus, HIF-1α and Epas1 expression levels were not significantly altered. Epas1 overexpression significantly increased Col2a1 expression. Both wild-type and Epas1+/− mice developed osteoarthritis following DMM surgery. There were no significant differences between genotypes at either time point. Conclusion The HIF pathway is likely not responsible for osteoarthritic changes in the human meniscus. Additionally, Epas1 insufficiency does not protect against osteoarthritis development in the mouse at early time points after DMM surgery. The HIF pathway may be more important for protection against catabolic stress.

scholarly journals Association of intronic DNA methylation and hydroxymethylation alterations in the epigenetic etiology of dilated cardiomyopathy

2019 ◽  
Vol 317 (1) ◽  
pp. H168-H180 ◽  
Author(s):  
Ali M. Tabish ◽  
Mohammed Arif ◽  
Taejeong Song ◽  
Zaher Elbeck ◽  
Richard C. Becker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dilated Cardiomyopathy ◽  
Cardiac Remodeling ◽  
Rna Seq ◽  
Wild Type ◽  
Kegg Pathways ◽  
Wild Type Phenotype ◽  
Gene Expression Levels

In this study, we investigated the role of DNA methylation [5-methylcytosine (5mC)] and 5-hydroxymethylcytosine (5hmC), epigenetic modifications that regulate gene activity, in dilated cardiomyopathy (DCM). A MYBPC3 mutant mouse model of DCM was compared with wild type and used to profile genomic 5mC and 5hmC changes by Chip-seq, and gene expression levels were analyzed by RNA-seq. Both 5mC-altered genes (957) and 5hmC-altered genes (2,022) were identified in DCM hearts. Diverse gene ontology and KEGG pathways were enriched for DCM phenotypes, such as inflammation, tissue fibrosis, cell death, cardiac remodeling, cardiomyocyte growth, and differentiation, as well as sarcomere structure. Hierarchical clustering of mapped genes affected by 5mC and 5hmC clearly differentiated DCM from wild-type phenotype. Based on these data, we propose that genomewide 5mC and 5hmC contents may play a major role in DCM pathogenesis. NEW & NOTEWORTHY Our data demonstrate that development of dilated cardiomyopathy in mice is associated with significant epigenetic changes, specifically in intronic regions, which, when combined with gene expression profiling data, highlight key signaling pathways involved in pathological cardiac remodeling and heart contractile dysfunction.

scholarly journals Distinct molecular etiologies of male and female hepatocellular carcinoma

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Heini M. Natri ◽  
Melissa A. Wilson ◽  
Kenneth H. Buetow
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Sex Differences ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Regulation Of Transcription ◽  
Male And Female ◽  
Differential Effects ◽  
Pathway Enrichment

Abstract Background Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Methods Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses. Results By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Conclusions Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

Role of Nucleophosmin Mutations in AML.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-13-sci-13 ◽  
Author(s):  
Kotaro Funato ◽  
David W. Sternberg
Keyword(s):  
Gene Expression ◽  
Translational Control ◽  
Ribosome Biogenesis ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Npm1 Mutation ◽  
Translational Initiation ◽  
Expression Signature ◽  
Anaplastic Lymphoma

Abstract Significant advances have been made towards understanding the molecular pathogenesis and prognostic determinants in acute myelogenous leukemia of normal karytype (AMLNK). One of these, somatic mutation within exon 12 of the nucleophosmin gene (NPM1), is present in 50–60% of AML-NK and has been associated with favorable response to induction chemotherapy, overall survival, and event-free survival, but only in the absence of FLT3-ITD mutation. In addition to exon 12 mutation, NPM1 is disrupted in hematologic malignancies through fusion to partner proteins such as the anaplastic lymphoma kinase (ALK), myeloid leukemia factor 1 in myelodysplasia (MLF1), and retinoic acid receptor-α (RARα). The NPM1 gene encodes a 37-kDa protein that is predominantly localized to the nucleolus but also shuttles to the nucleoplasm and cytoplasm. A strong association (perhaps a 100% correlation) exists between NPM1 mutation and aberrant localization of the nucleophosmin protein in the cytoplasm. This mislocalization of nucleophosmin has been attributed to the loss of tryptophan residues 288 and 290 (or 290 only) in the carboxy terminus of this protein, and these motifs are required for nucleolar localization of nucleophosmin. Importantly, the NPM1 mutation also creates a de novo nuclear export signal within nucleophosmin. The functional role of wild-type nucleophosmin has been implicated in the regulation of cell growth control through p14ARF and p53 interactions, ribosome biogenesis, centrosome duplication, as well as other functions. Pediatric AML samples with NPM1 mutation were reported to have a distinct gene expression signature, including altered expression of homeobox (HOX) genes, and adult AML specimens carrying mutant NPM1 were reported to have a distinct microRNA expression signature. In addition to alterations in the expression of mRNA and microRNA species, the critical function of nucleophosmin in ribosome biogenesis, as well as its reported association with poly(A)(+) mRNA’s in vivo, suggests that mutant NPM1 could disrupt gene expression through aberrant translational control. Regulators of translational initiation can be rate-limiting for neoplasia in animal models, and we evaluated the hypothesis that cytoplasmic nucleophosmin promotes leukemogenesis by similarly altering the translational control of gene expression. Here, we present data to show that enforced expression of mutant nucleophosmin significantly alters the partitioning of mRNA’s to polyribosomes. Polyribosomal extracts were purified from cells that express wild-type or mutant nucleophosmin, RNA was extracted from this material, and the global profile of mRNA in these fractions was evaluated by gene expression microarray analysis. Enforced expression of cytoplasmic nucleophosmin significantly altered mRNA recruitment to polysomes. Moreover, we found common features in the polysome signature of cells expressing mutant NPM or the NPM-ALK fusion, suggesting that cytoplasmic NPM and the NPM-ALK fusion might disrupt translational initiation through partially overlapping mechanisms. These findings suggest that mutant nucleophosmin can perturb mRNA translational initiation in concert with other molecular mechanisms in the pathogenesis of AML-NK.

Desialylated Platelets Are Cleared From the Circulation by the Hepatic Asialoglycoprotein Receptor,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3257-3257
Author(s):  
Renata Grozovsky ◽  
Silvia Giannini ◽  
Karin M. Hoffmeister
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Fold Increase ◽  
Asialoglycoprotein Receptor ◽  
Regulatory Mechanisms ◽  
Wild Type ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
Terminal Galactose

Abstract Abstract 3257 The regulatory mechanisms of platelet homeostasis remain elusive. We investigated here the role of hepatic asialoglycoprotein receptor (a.k.a. Ashwell-Morell receptor) in platelet clearance. Mice lacking the hepatic asialoglycoprotein receptor Asgpr2 subunit had increased platelet survivals (T1/2 = 49.5±2h) when compared to wild type (WT, T1/2 = 31±4h) mice. Consequently, Asgpr2−/− mice had platelet counts increased by ∼20%, compared to WT, with increased terminal galactose exposure, as demonstrated using the galactose specific lectin RCA1. Bone marrow and spleen megakaryocyte numbers were reduced by ∼15% and ∼20% in Asgpr2−/− mice, compared to WT mice. Sialidase (NA, Clostidium perfringens, 50mU/mice) maximally desialylated circulating platelets when injected intravenously, as evidenced by increased RCA1 binding. Sialidase injection resulted in a ∼60% depletion of circulating platelets after 24h in Asgpr2−/− mice, compared to >90% in WT mice, indicating that desialylated platelets were partially removed by Asgpr1/2. In contrast to platelets, red blood cell counts were unaffected by sialidase treatment. Sialidase injection for 72h resulted in a 2.3-fold and 1.2-fold increase in megakaryocyte numbers in the spleen and bone marrow of WT mice, respectively, but not in Asgpr2−/− mice. In contrast to sialidase treatment, injections of rabbit anti-mouse platelet serum (RAMPS) depleted >95% of circulating platelets and increased by 70% bone marrow, but not spleen MK numbers in both WT and Asgpr2−/− mice. The data shows that removal of desialylated, i.e, senescent, platelets by the hepatic Ashwell-Morell receptor differs to that of antibody-mediated platelet clearance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role of σD in Regulating Genes and Signals during Myxococcus xanthus Development

2006 ◽  
Vol 188 (9) ◽  
pp. 3246-3256 ◽  
Author(s):  
Poorna Viswanathan ◽  
Mitchell Singer ◽  
Lee Kroos
Keyword(s):  
Gene Expression ◽  
Rna Polymerase ◽  
Biofilm Formation ◽  
Myxococcus Xanthus ◽  
Control Cell ◽  
Wild Type ◽  
Developmental Genes ◽  
Measuring Signal ◽  
Early Developmental

ABSTRACT Starvation-induced development of Myxococcus xanthus is an excellent model for biofilm formation because it involves cell-cell signaling to coordinate formation of multicellular mounds, gene expression, and cellular differentiation into spores. The role of σD, an alternative σ factor important for viability in stationary phase and for stress responses, was investigated during development by measuring signal production, gene expression, and sporulation of a sigD null mutant alone and upon codevelopment with wild-type cells or signaling mutants. The sigD mutant responded to starvation by inducing (p)ppGpp synthesis normally but was impaired for production of A-signal, an early cell density signal, and for production of the morphogenetic C-signal. Induction of early developmental genes was greatly reduced, and expression of those that depend on A-signal was not restored by codevelopment with wild-type cells, indicating that σD is needed for cellular responses to A-signal. Despite these early developmental defects, the sigD mutant responded to C-signal supplied by codeveloping wild-type cells by inducing a subset of late developmental genes. σD RNA polymerase is dispensable for transcription of this subset, but a distinct regulatory class, which includes genes essential for sporulation, requires σD RNA polymerase or a gene under its control, cell autonomously. The level of sigD transcript in a relA mutant during growth is much lower than in wild-type cells, suggesting that (p)ppGpp positively regulates sigD transcription in growing cells. The sigD transcript level drops in wild-type cells after 20 min of starvation and remains low after 40 min but rises in a relA mutant after 40 min, suggesting that (p)ppGpp negatively regulates sigD transcription early in development. We conclude that σD synthesized during growth occupies a position near the top of a regulatory hierarchy governing M. xanthus development, analogous to σ factors that control biofilm formation of other bacteria.

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