The mEPN scheme: an intuitive and flexible graphical system for rendering biological pathways

Abstract

Background: There is general agreement amongst biologists about the need for good pathway diagrams and a need to formalize the way biological pathways are depicted. However, implementing and agreeing how best to do this is currently the subject of some debate.

Results: The modified Edinburgh Pathway Notation (mEPN) scheme is founded on a notation system originally devised a number of years ago and through use has now been refined extensively. This process has been primarily driven by the author's attempts to produce process diagrams for a diverse range of biological pathways, particularly with respect to immune signaling in mammals. Here we provide a specification of the mEPN notation, its symbols, rules for its use and a comparison to the proposed Systems Biology Graphical Notation (SBGN) scheme.

Conclusions: We hope this work will contribute to the on-going community effort to develop a standard for depicting pathways and will provide a coherent guide to those planning to construct pathway diagrams of their biological systems of interest.

Figure 1

List of the Glyphs used by the modified Edinburgh Pathway Notation (mEPN) scheme. Unique shapes and identifiers are used to distinguish between each element of the notation scheme. The notation scheme essentially consists of the following categories of nodes representing; cellular components, compartments, Boolean logic, edge annotations, reactions and processes. For a full description of the notation scheme and rules for its use see Additional files 1 and 2.

Figure 2

Graphical Representation of Complexes. (A) Two alternate views of the STAT1 homodimer both of which would be considered to be formally correct under the mEPN scheme. (B) Visual representation of interferon-gamma receptor complex bound to IFNG. For membrane receptor complexes such this we have generally favoured showing the complexes spanning the plasma membrane (brown) with the receptor portion protruding into the extra-cellular space (grey) and with the adaptor molecules projecting into the cytoplasm (yellow). (C) The 26S proteasome has a barrel-like structure made up of 6 six concentric rings each composed of 7 proteasome subunits, capped with regulatory subunits at either end. We therefore chose to arrange the subunit in names in this manner so as to capture visually something of this arrangement. (D) Model of the transcription factor/coactivator complex that regulate genes associated with MHC class2 antigen presentation such as CD74. In this case transcription is thought to be regulated by two transcription factor complexes, CREB1 and one unknown factor which bind directly to four elements in the gene's promoter and transcription is initiated by a conformation change induced by the binding of CIITA. Here as in E interaction edges are used to denote a physical link between components of the complex. (E) DNA replication complex formed during S-phase. As complexes become large the use of the physical interaction edge becomes essential in defining not only which components make up the complex but where in the complex they reside. This arrangement also allows for the depiction of specific components of the complex to undergo a change in state or cause a change in another component (which may or may not be part of the same complex).

Figure 3

Graphical Representation of the Interferon-gamma Pathway Leading to MHC class 2 Antigen Presentation. Shown here are the known events between the release of IFNγ and the subsequent up-regulation of MHC class 2 antigen presentation by macrophages using the mEPN scheme. See results for a full description of this pathway.

Figure 4

mEPN^3D Scheme. Presented here is a conversion of the standard mEPN scheme into a series of shapes that can be used to depict the same pathway concepts in 3D environments.

Figure 5

Pathway Representation in 3D Environment. Large macrophage activation pathway rendered in 3D environment where node shape, size and colour represents a components identity. (A) Nodes coloured according to type e.g. light blue - proteins, yellow - protein complexes, purple - generic molecular species. All process nodes are depicted as small cubes and coloured according to type. (B) Nodes coloured according to cellular location e.g. brown - plasma membrane, yellow - cytoplasm, purple - endosome, green nucleus. Process nodes/Boolean logic operators are shown as having no cellular location and are coloured dark blue (no class). (C) Nodes coloured according to overlay of data, in this case expression data. Colour of nodes represents co-expression cluster following stimulation of mouse macrophages with Ifnβ (D) A representation of the interferon-beta signalling pathway and the transcriptional network it controls. The signalling network is represented using the mEPN^3D notation with the addition of transition nodes for use in modelling studies. Connected to it are clusters of genes up or down regulated by Ifnb which have been stacked in at different layers depending on the their time course of activation/repression.

Figure 6

Comparison of mEPN to SBGN. Main glyphs used in the mEPN shown on the left, SBGN glyphs on the right. (A) Shows the main symbols used for depicting biological entities and (B) the different ways the two schemes represent protein complexes. (C) Different way of showing edge meaning and (D) the different symbols used to depict various processes. mEPN names for these entities/activities given alongside and SBGN names, when different, in brackets beneath. For a more in depth comparison of the two notation schemes see Additional file 4.