Acetylation of histones at DNA regulatory elements plays a critical role in transcriptional activation. Histones are also modified by other acyl moieties, including crotonyl, yet the mechanisms that ...govern acetylation versus crotonylation and the functional consequences of this “choice” remain unclear. We show that the coactivator p300 has both crotonyltransferase and acetyltransferase activities, and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Levels of histone crotonylation are regulated by the cellular concentration of crotonyl-CoA, which can be altered through genetic and environmental perturbations. In a cell-based model of transcriptional activation, increasing or decreasing the cellular concentration of crotonyl-CoA leads to enhanced or diminished gene expression, respectively, which correlates with the levels of histone crotonylation flanking the regulatory elements of activated genes. Our findings support a general principle wherein differential histone acylation (i.e., acetylation versus crotonylation) couples cellular metabolism to the regulation of gene expression.
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•The histone acetyltransferase p300 also regulates histone crotonylation•Histone crotonylation directly stimulates transcription•Histone crotonylation is regulated by the concentration of crotonyl-CoA•Local changes in differential histone acylation influence gene expression
Sabari et al. establish a direct role for histone crotonylation in the stimulation of transcription and demonstrate that the modification is regulated enzymatically by p300/CBP and metabolically by the availability of crotonyl-CoA.
Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of ...citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed, and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.
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•Glutamine depletion-induced apoptosis results from asparagine depletion•Reducing citrate synthase levels promotes aspartate/asparagine biosynthesis•Asparagine is sufficient to suppress apoptosis in response to glutamine depletion•Asparagine promotes ATF4-dependent adaptive stress responses
Many cancer cells require glutamine for survival even though it is a nonessential amino acid. Using RNAi screening and subsequent investigation, Zhang et al. identify that asparagine is necessary and sufficient to suppress apoptosis in glutamine-deprived cells. In vivo, asparagine synthetase expression is correlated with poor prognosis in human tumors.
Cysteine acts both as a building unit for protein translation and as the limiting substrate for glutathione synthesis to support the cellular antioxidant system. In addition to transporter-mediated ...uptake, cellular cysteine can also be synthesized from methionine through the transsulfuration pathway. Here, we investigate the regulation of transsulfuration and its role in sustaining cell proliferation upon extracellular cysteine limitation, a condition reported to occur in human tumors as they grow in size. We observed constitutive expression of transsulfuration enzymes in a subset of cancer cell lines, while in other cells, these enzymes are induced following cysteine deprivation. We show that both constitutive and inducible transsulfuration activities contribute to the cellular cysteine pool and redox homeostasis. The rate of transsulfuration is determined by the cellular capacity to conduct methylation reactions that convert S-adenosylmethionine to S-adenosylhomocysteine. Finally, our results demonstrate that transsulfuration-mediated cysteine synthesis is critical in promoting tumor growth in vivo.
The Chlamydomonas cell cycle Cross, Frederick R.; Umen, James G.
Plant journal,
20/May , Volume:
82, Issue:
3
Journal Article
Peer reviewed
Open access
Summary
The position of Chlamydomonas within the eukaryotic phylogeny makes it a unique model in at least two important ways: as a representative of the critically important, early‐diverging lineage ...leading to plants; and as a microbe retaining important features of the last eukaryotic common ancestor (LECA) that has been lost in the highly studied yeast lineages. Its cell biology has been studied for many decades and it has well‐developed experimental genetic tools, both classical (Mendelian) and molecular. Unlike land plants, it is a haploid with very few gene duplicates, making it ideal for loss‐of‐function genetic studies. The Chlamydomonas cell cycle has a striking temporal and functional separation between cell growth and rapid cell division, probably connected to the interplay between diurnal cycles that drive photosynthetic cell growth and the cell division cycle; it also exhibits a highly choreographed interaction between the cell cycle and its centriole–basal body–flagellar cycle. Here, we review the current status of studies of the Chlamydomonas cell cycle. We begin with an overview of cell‐cycle control in the well‐studied yeast and animal systems, which has yielded a canonical, well‐supported model. We discuss briefly what is known about similarities and differences in plant cell‐cycle control, compared with this model. We next review the cytology and cell biology of the multiple‐fission cell cycle of Chlamydomonas. Lastly, we review recent genetic approaches and insights into Chlamydomonas cell‐cycle regulation that have been enabled by a new generation of genomics‐based tools.
Significance Statement
Chlamydomonas is an excellent model for many areas of eukaryotic biology, including the cell cycle. Its phylogenetic position in the green lineage and its utility as a microbial genetic system give this organism great potential for addressing unanswered questions about eukaryotic cell cycle control and for defining new regulatory mechanisms that govern cell cycle progression.
It is accepted that non-avian theropod dinosaurs, with their long muscular tails and small forelimbs, had a centre-of-mass close to the hip, while extant birds, with their reduced tails and enlarged ...wings have their mass centred more cranially. Transition between these states is considered crucial to two key innovations in the avian locomotor system: crouched bipedalism and powered flight. Here we use image-based models to challenge this dichotomy. Rather than a phylogenetic distinction between 'dinosaurian' and 'avian' conditions, we find terrestrial versus volant taxa occupy distinct regions of centre-of-mass morphospace consistent with the disparate demands of terrestrial bipedalism and flight. We track this decoupled evolution of body shape and mass distribution through bird evolution, including the origin of centre-of-mass positions more advantageous for flight and major reversions coincident with terrestriality. We recover modularity in the evolution of limb proportions and centre-of-mass that suggests fully crouched bipedalism evolved after powered flight.
The spindle assembly checkpoint (SAC) delays anaphase onset until kinetochores accomplish bioriented microtubule attachments 1. Although several centromeric and kinetochore kinases, including Aurora ...B, regulate kinetochore-microtubule attachment and/or SAC activation 2–4, the molecular mechanism that translates bioriented attachment into SAC silencing remains unclear 5. Employing a method to rapidly induce exact gene replacement in budding yeast 6, we show here that the binding of protein phosphatase 1 (PP1/Glc7) to the evolutionarily conserved RVSF motif of the kinetochore protein Spc105 (KNL1/Blinkin/CASC5) is essential for viability by silencing the SAC, while it plays an auxiliary nonessential role for physical chromosome segregation. Although Aurora B may inhibit this binding, persistent PP1-Spc105 interaction does not affect chromosome segregation and is insufficient to silence the SAC in the absence of microtubules, indicating that dynamic regulation of this interaction is dispensable. However, the amount of PP1 targeted to kinetochores must be finely tuned, because recruitment of either no or one extra copy of PP1 to Spc105 is detrimental, illustrating the vital impact of targeting an exiguous fraction of PP1 to the kinetochore. We propose that the PP1-Spc105 interaction enables local regulation of dynamic phosphorylation and dephosphorylation at the kinetochore to couple microtubule attachment and SAC silencing.
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► PP1 must bind KNL1/Spc105 in order to silence the SAC ► Spc105-PP1 interaction is insufficient to silence the SAC without microtubules ► Negative regulation of this interaction by Aurora B is dispensable in mitosis ► The amount of PP1 recruited to the kinetochore must be finely tuned
Attitudes are often referred to, researched and considered in the discipline of health education and health promotion. This paper highlights Q methodology as an appropriate and relevant means of ...exploring and studying attitudes within this field. It begins by discussing the difficulties in defining attitude and the problems inherent in attitude measurement. A brief history of Q methodology is given, followed by an explanation of what Q methodology is and the processes involved. This paper argues the case for the use of Q methodology when studying attitudes and justifies why Q methodology should particularly be selected in the study of attitudes within the health field. There are many reasons for this assertion which are explored throughout the paper. The principle one is that Q methodology is a more robust technique, than alternative methods, for the measurement of attitudes and subjective opinion. This paper concludes by proposing that Q methodology is taken up by researchers within health education and health promotion who are concerned with exploring attitudes and subjective opinion.
Connections between the gut and brain monitor the intestinal tissue and its microbial and dietary content
, regulating both physiological intestinal functions such as nutrient absorption and motility
..., and brain-wired feeding behaviour
. It is therefore plausible that circuits exist to detect gut microorganisms and relay this information to areas of the central nervous system that, in turn, regulate gut physiology
. Here we characterize the influence of the microbiota on enteric-associated neurons by combining gnotobiotic mouse models with transcriptomics, circuit-tracing methods and functional manipulations. We find that the gut microbiome modulates gut-extrinsic sympathetic neurons: microbiota depletion leads to increased expression of the neuronal transcription factor cFos, and colonization of germ-free mice with bacteria that produce short-chain fatty acids suppresses cFos expression in the gut sympathetic ganglia. Chemogenetic manipulations, translational profiling and anterograde tracing identify a subset of distal intestine-projecting vagal neurons that are positioned to have an afferent role in microbiota-mediated modulation of gut sympathetic neurons. Retrograde polysynaptic neuronal tracing from the intestinal wall identifies brainstem sensory nuclei that are activated during microbial depletion, as well as efferent sympathetic premotor glutamatergic neurons that regulate gastrointestinal transit. These results reveal microbiota-dependent control of gut-extrinsic sympathetic activation through a gut-brain circuit.
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