Designing sequential transcription logic: a simple genetic circuit for conditional memory

Abstract

The ability to learn and respond to recurrent events depends on the capacity to remember transient biological signals received in the past. Moreover, it may be desirable to remember or ignore these transient signals conditioned upon other signals that are active at specific points in time or in unique environments. Here, we propose a simple genetic circuit in bacteria that is capable of conditionally memorizing a signal in the form of a transcription factor concentration. The circuit behaves similarly to a ''data latch'' in an electronic circuit, i.e. it reads and stores an input signal only when conditioned to do so by a ''read command.'' Our circuit is of the same size as the well-known genetic toggle switch (an unconditional latch) which consists of two mutually repressing genes, but is complemented with a ''regulatory front end'' involving protein heterodimerization as a simple way to implement conditional control. Deterministic and stochastic analysis of the circuit dynamics indicate that an experimental implementation is feasible based on well-characterized genes and proteins. It is not known, to which extent molecular networks are able to conditionally store information in natural contexts for bacteria. However, our results suggest that such sequential logic elements may be readily implemented by cells through the combination of existing protein-protein interactions and simple transcriptional regulation.

Biological Signal Processing with a Genetic Toggle Switch

“…A previous theoretical analysis [24] has shown that simple combinations of protein-DNA and protein-protein interactions suffice to turn a genetic toggle switch into a conditional memory unit, which memorizes a signal only when given a read “command”, akin to a Data latch in digital electronics. Here, we explore whether the same set of interactions also enable the design of a toggle command, which is intrinsically more complex, since it makes the output dependent on the memorized signal.…”

“…In particular, for the core memory unit of Fig. 1A, we chose a ‘genetic toggle switch’ consisting of two mutually repressing genes, the implementation of which was one of the first milestones in synthetic biology [22] and served as the basis for simple sequential logics [23], [24]. Genetic switches of this kind have later also been identified as important elements of the Drosophila gap gene network [25].…”

Taming Living Logic Using Formal Methods

“…The standard part libraries and toolboxes of well-characterized genetic components have been constructed through numerous laboratory experiments over the last decade [10][11][12][13][14][15][16][17][18]. These components have been extensively used to develop genetic circuits with different functionalities including oscillators [3], amplifiers [19,20], linearizer gene circuit [21], memory devices [22,23], switches [1,12,24], time-delay circuits [25,26], genetic logic gates [27][28][29][30] etc. …”

Stochasticity, Bistability and the Wisdom of Crowds: A Model for Associative Learning in Genetic Regulatory Networks

“…The capacity of GRNs to learn associations in shorter, non-evolutionary time-scales has also been studied theoretically using GRN models. Learning in these models is restricted to a small subset of predefined stimuli [18], [19], [20], [21] and thus the computational capabilities of these GRN models are limited compared to neural network models.…”