Michael Eisen is exasperated with the compound word “spatiotemporal”.  “Can we invent or appropriate something better?”, he asks.  Over the next several posts, I’ll present an example of spatiotemporal gene regulation, techniques for analyzing and modeling it, and suggest a few metaphors that might lead to “nicer” words.

Part 1: Spatiotemporal Transcriptional Logic

Consider the marvelous spatiotemporal program an organism’s genome must encode to organize embryogenesis and development.  Cells divide and specialize, divide and specialize, recursively executing the developmental program stored in the genome according variables mediated by time and space.

This process is reliable and repeatable: for instance, (under normal growth conditions), wild-type C. elegens develops into precisely 959 somatic cells, for each of which the lineage and developmental fate is known.   The implications continue to amaze me – is development really so deterministic?!

Davidson College’s Genomics class introduced the notion of spatiotemporal logic with an in-depth analysis of the genetic control regions of a Sea Urchin gene called Endo16.  Eric Davidson’s lab essentially spent years reverse engineering the genetic logic controlling Endo16′s expression in developing Sea Urchin embryos.  They elucidated the identity of modular patterns of regulatory DNA upstream of Endo16.  These regulatory modules act as inputs for a variety of transcription factors.  To understand the transcriptional logic encoded by the pattern of regulatory modules, the Davidson team quantitatively measured the effect different transcription factor combinations had on the output of the regulatory region i.e. expression of Endo16.   The logic they deduced was so coherent they were able to write it in pseudocode.

Here is a diagram from one of their papers describing the transcriptional logic:

Let me quote from the introduction of their paper:

Each gene, in each cell of a developing animal, must read and respond to the presence or absence of multiple inputs. In effect, these inputs provide the gene with the regulatory information it requires to determine its own activity: this includes signaling inputs from adjacent cells and inputs that indicate what other relevant genes have been functioning in the cell in which the gene resides. These inputs are presented to the gene in terms of concentrations and activities of nuclear transcription factors. The heritable structural basis for cis-regulatory information processing functions consists of the target site sequences at which transcription factors bind to the DNA. The identity and disposition of these sites specify the regulatory activities that can be executed by the cis-regulatory system, depending on circumstances. This genetic hardwiring causally determines to which inputs each gene regulatory system will (Davidson, 1990; Davidson, 1999; Davidson, 2001).

So essentially, the spatial and temporal variation in transcription factors are the inputs for logic gates controlling gene expression.  Sound interesting?  The next step is to check out The regulatory genome and the computer, a review the Davidson team wrote in 2007 that is in ways the genomics version of Von Neumann’s The Computer and the Brain.  I’ll leave you with the abstract:

The definitive feature of the many thousand cis-regulatory control modules in an animal genome is their information processing capability. These modules are “wired” together in large networks that control major processes such as development; they constitute “genomic computers.” Each control module receives multiple inputs in the form of the incident transcription factors which bind to them. The functions they execute upon these inputs can be reduced to basic AND, OR and NOT logic functions, which are also the unit logic functions of electronic computers. Here we consider the operating principles of the genomic computer, the product of evolution, in comparison to those of electronic computers. For example, in the genomic computer intra-machine communication occurs by means of diffusion (of transcription factors), while in electronic computers it occurs by electron transit along pre-organized wires. There follow fundamental differences in design principle in respect to the meaning of time, speed, multiplicity of processors, memory, robustness of computation and hardware and software. The genomic computer controls spatial gene expression in the development of the body plan, and its appearance in remote evolutionary time must be considered to have been a founding requirement for animal grade life.