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A dynamic model of transcriptional imprinting derived from the vitellogenesis memory effect.

ABSTRACT: Transcriptional memory of transient signals can be imprinted on living systems and influence their reactivity to repeated stimulations. Although they are classically ascribed to structural chromatin rearrangements in eukaryotes, such behaviors can also rely on dynamic memory circuits with sustained self-amplification loops. However, these phenomena are either of finite duration, or conversely associated to sustained phenotypic changes. A mechanism is proposed, in which only the responsiveness of the target gene is durably reset at a higher level after primary stimulation, using the celebrated but still puzzling vitellogenesis memory effect. The basic ingredients of this system are: 1), a positive autoregulation of the estrogen receptor ? gene; 2), a strongly cooperative action of the estradiol receptor on vitellogenin expression; and 3), a variant isoform of the estradiol receptor with two autonomous transcription-activating modules, one of which is signal-independent and the other, signal-dependent. Realistic quantification supports the possibility of a multistationary situation in which ligand-independent activity is unable by itself to prime the amplification loop, but can click the system over a memory threshold after a primary stimulation. This ratchet transcriptional mechanism can have developmental and ecotoxicological importance and explain lifelong imprinting of past exposures without apparent phenotypic changes before restimulation and without need for persistent chromatin modifications.

SUBMITTER: Nicol-Benoit F

PROVIDER: S-EPMC3183801 | biostudies-other | 2011 Oct

REPOSITORIES: biostudies-other

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A dynamic model of transcriptional imprinting derived from the vitellogenesis memory effect.

Nicol-Benoit Floriane F Amon Axelle A Vaillant Colette C le Goff Pascale P le Dréan Yves Y Pakdel Farzad F Flouriot Gilles G Valotaire Yves Y Michel Denis D

Biophysical journal 20111001 7

Transcriptional memory of transient signals can be imprinted on living systems and influence their reactivity to repeated stimulations. Although they are classically ascribed to structural chromatin rearrangements in eukaryotes, such behaviors can also rely on dynamic memory circuits with sustained self-amplification loops. However, these phenomena are either of finite duration, or conversely associated to sustained phenotypic changes. A mechanism is proposed, in which only the responsiveness of ...[more]

PMID: 21961581

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Project description:Previous studies have described a transcriptional "memory effect," whereby transcript levels of many Abf1-regulated genes in the budding yeast Saccharomyces cerevisiae are undiminished even after Abf1 has dissociated from its regulatory sites. Here we provide additional support for this effect and investigate its molecular basis. We show that the effect is observed in a distinct abf1 ts mutant from that used in earlier studies, demonstrating that it is robust, and use chromatin immunoprecipitation to show that Abf1 association is decreased similarly from memory effect and transcriptionally responsive genes at the restrictive temperature. We also demonstrate that the association of TATA-binding protein and Pol II decreases after the loss of Abf1 binding for transcriptionally responsive genes but not for memory effect genes. Examination of genome-wide nucleosome occupancy data reveals that although transcriptionally responsive genes exhibit increased nucleosome occupancy in abf1 ts yeast, the promoter regions of memory effect targets show no change in abf1 ts mutants, maintaining an open chromatin conformation even after Abf1 eviction. This contrasting behavior reflects different inherent propensity for nucleosome formation between the two classes, driven by the presence of A/T-rich sequences upstream of the Abf1 site in memory effect gene promoters. These sequence-based differences show conservation in closely related fungi and also correlate with different gene expression noise, suggesting a physiological basis for greater access to "memory effect" promoter regions. Thus, our results establish a conserved mechanism underlying a transcriptional memory effect whereby sequences surrounding Abf1 binding sequences affect local nucleosome occupancy following loss of Abf1 binding. Furthermore, these findings demonstrate that sequence-based differences in the propensity for nucleosome occupancy can influence the transcriptional response of genes to an altered regulatory signal.

Project description:BACKGROUND: Cellular signaling involves a sequence of events from ligand binding to membrane receptors through transcription factors activation and the induction of mRNA expression. The transcriptional-regulatory system plays a pivotal role in the control of gene expression. A novel computational approach to the study of gene regulation circuits is presented here. METHODOLOGY: Based on the concept of finite state machine, which provides a discrete view of gene regulation, a novel sequential logic model (SLM) is developed to decipher control mechanisms of dynamic transcriptional regulation of gene expressions. The SLM technique is also used to systematically analyze the dynamic function of transcriptional inputs, the dependency and cooperativity, such as synergy effect, among the binding sites with respect to when, how much and how fast the gene of interest is expressed. PRINCIPAL FINDINGS: SLM is verified by a set of well studied expression data on endo16 of Strongylocentrotus purpuratus (sea urchin) during the embryonic midgut development. A dynamic regulatory mechanism for endo16 expression controlled by three binding sites, UI, R and Otx is identified and demonstrated to be consistent with experimental findings. Furthermore, we show that during transition from specification to differentiation in wild type endo16 expression profile, SLM reveals three binary activities are not sufficient to explain the transcriptional regulation of endo16 expression and additional activities of binding sites are required. Further analyses suggest detailed mechanism of R switch activity where indirect dependency occurs in between UI activity and R switch during specification to differentiation stage. CONCLUSIONS/SIGNIFICANCE: The sequential logic formalism allows for a simplification of regulation network dynamics going from a continuous to a discrete representation of gene activation in time. In effect our SLM is non-parametric and model-independent, yet providing rich biological insight. The demonstration of the efficacy of this approach in endo16 is a promising step for further application of the proposed method.

Dataset Information

A dynamic model of transcriptional imprinting derived from the vitellogenesis memory effect.

Publications

A dynamic model of transcriptional imprinting derived from the vitellogenesis memory effect.

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