اشترك بالحزمة الذهبية واحصل على وصول غير محدود شمرا أكاديميا
تسجيل مستخدم جديدDNA Supercoiling Drives a Transition between Collective Modes of Gene Synthesis
168
0
0.0
(
0
)
اسأل ChatGPT حول البحث
ﻻ يوجد ملخص باللغة العربية
Recent experiments showed that multiple copies of the molecular machine RNA polymerase (RNAP) can efficiently synthesize mRNA collectively in the active state of the promoter. However, environmentally-induced promoter repression results in long-distance antagonistic interactions that drastically reduce the speed of RNAPs and cause a quick arrest of mRNA synthesis. The mechanism underlying this transition between cooperative and antagonistic dynamics remains poorly understood. In this Letter, we introduce a continuum deterministic model for the translocation of RNAPs, where the speed of an RNAP is coupled to the local DNA supercoiling as well as the density of RNAPs on the gene. We assume that torsional stress experienced by individual RNAPs is exacerbated by high RNAP density on the gene and that transcription factors act as physical barriers to the diffusion of DNA supercoils. We show that this minimal model exhibits two transcription modes mediated by the torsional stress: a fluid mode when the promoter is active and a torsionally stressed mode when the promoter is repressed, in quantitative agreement with experimentally observed dynamics of co-transcribing RNAPs. Our work provides an important step towards understanding the collective dynamics of molecular machines involved in gene expression.
قيم البحث
اقرأ أيضاً
We assess the impact of cell cycle noise on gene circuit dynamics. For bistable genetic switches and excitable circuits, we find that transitions between metastable states most likely occur just after cell division and that this concentration effect
intensifies in the presence of transcriptional delay. We explain this concentration effect with a 3-states stochastic model. For genetic oscillators, we quantify the temporal correlations between daughter cells induced by cell division. Temporal correlations must be captured properly in order to accurately quantify noise sources within gene networks.
We study theoretically the effects of confinement on active polar gels such as the actin network of eukaryotic cells. Using generalized hydrodynamics equations derived for active gels, we predict, in the case of quasi one-dimensional geometry, a spon
taneous flow transition from a homogeneously polarized immobile state for small thicknesses, to a perturbed flowing state for larger thicknesses. The transition is not driven by an external field but by the activity of the system. We suggest several possible experimental realizations.
The detection of sound begins when energy derived from acoustic stimuli deflects the hair bundles atop hair cells. As hair bundles move, the viscous friction between stereocilia and the surrounding liquid poses a fundamental challenge to the ears hig
h sensitivity and sharp frequency selectivity. Part of the solution to this problem lies in the active process that uses energy for frequency-selective sound amplification. Here we demonstrate that a complementary part involves the fluid-structure interaction between the liquid within the hair bundle and the stereocilia. Using force measurement on a dynamically scaled model, finite-element analysis, analytical estimation of hydrodynamic forces, stochastic simulation and high-resolution interferometric measurement of hair bundles, we characterize the origin and magnitude of the forces between individual stereocilia during small hair-bundle deflections. We find that the close apposition of stereocilia effectively immobilizes the liquid between them, which reduces the drag and suppresses the relative squeezing but not the sliding mode of stereociliary motion. The obliquely oriented tip links couple the mechanotransduction channels to this least dissipative coherent mode, whereas the elastic horizontal top connectors stabilize the structure, further reducing the drag. As measured from the distortion products associated with channel gating at physiological stimulation amplitudes of tens of nanometres, the balance of forces in a hair bundle permits a relative mode of motion between adjacent stereocilia that encompasses only a fraction of a nanometre. A combination of high-resolution experiments and detailed numerical modelling of fluid-structure interactions reveals the physical principles behind the basic structural features of hair bundles and shows quantitatively how these organelles are adapted to the needs of sensitive mechanotransduction.
Although accumulation of molecular damage is suggested to be an important molecular mechanism of aging, a quantitative link between the dynamics of damage accumulation and mortality of species has so far remained elusive. To address this question, we
examine stability properties of a generic gene regulatory network (GRN) and demonstrate that many characteristics of aging and the associated population mortality rate emerge as inherent properties of the critical dynamics of gene regulation and metabolic levels. Based on the analysis of age-dependent changes in gene-expression and metabolic profiles in Drosophila melanogaster, we explicitly show that the underlying GRNs are nearly critical and inherently unstable. This instability manifests itself as aging in the form of distortion of gene expression and metabolic profiles with age, and causes the characteristic increase in mortality rate with age as described by a form of the Gompertz law. In addition, we explain late-life mortality deceleration observed at very late ages for large populations. We show that aging contains a stochastic component, related to accumulation of regulatory errors in transcription/translation/metabolic pathways due to imperfection of signaling cascades in the network and of responses to environmental factors. We also establish that there is a strong deterministic component, suggesting genetic control. Since mortality in humans, where it is characterized best, is strongly associated with the incidence of age-related diseases, our findings support the idea that aging is the driving force behind the development of chronic human diseases.
Gene-gene interactions have long been recognized to be fundamentally important to understand genetic causes of complex disease traits. At present, identifying gene-gene interactions from genome-wide case-control studies is computationally and methodo
logically challenging. In this paper, we introduce a simple but powerful method, named `BOolean Operation based Screening and Testing(BOOST). To discover unknown gene-gene interactions that underlie complex diseases, BOOST allows examining all pairwise interactions in genome-wide case-control studies in a remarkably fast manner. We have carried out interaction analyses on seven data sets from the Wellcome Trust Case Control Consortium (WTCCC). Each analysis took less than 60 hours on a standard 3.0 GHz desktop with 4G memory running Windows XP system. The interaction patterns identified from the type 1 diabetes data set display significant difference from those identified from the rheumatoid arthritis data set, while both data sets share a very similar hit region in the WTCCC report. BOOST has also identified many undiscovered interactions between genes in the major histocompatibility complex (MHC) region in the type 1 diabetes data set. In the coming era of large-scale interaction mapping in genome-wide case-control studies, our method can serve as a computationally and statistically useful tool.
سجل دخول لتتمكن من نشر تعليقات
التعليقات
جاري جلب التعليقات
سجل دخول لتتمكن من متابعة معايير البحث التي قمت باختيارها
