Temporal combinations of transcription factors as a mechanism for neuronal diversification.
Transcription factors (TFs), play indisputable roles in the expression of different terminal gene sets, typically acting in a combinatorial manner. Such combinatorial or intersectional use of TFs is a widespread strategy for specifying distinct cell types. Most cases of combinatorial activity represent spatial intersections, in which two or more TFs are co- expressed and jointly required to activate transcription of a given locus. However, while studying the development of two sensory neurons in C. elegans, we discovered a novel type of combinatorial activity, that we termed temporal intersection (Cochella & Hobert, Cell 2012; Charest et al. Dev. Cell 2020) . In this mechanism, the transient binding of an early TF leaves a “memory” of activation that can then be boosted by a later acting TF. This relies on changes in chromatin states and TF binding abilities that we are beginning to unravel using newly tailored means of manipulation and molecular readouts.
The combinatorial action of temporally separated TFs has two important implications: i) not only the terminally expressed genes, but also the transcriptional history of a cell defines its identity, and ii) because cells are specified through progenitors that go through different transcriptional states, a vast number of TF combinations over time is possible, and may contribute to diversifying cell types during development. We thus propose that temporal intersections, like spatial intersections, broadly contribute to neuronal diversity.
Relevant publications:
- Combinatorial Action of Temporally Segregated Transcription Factors.
Charest J, Daniele T, Wang J, Bykov A, Mandlbauer A, Asparuhova M, Röhsner J, Gutiérrez-Pérez P, Cochella L Dev Cell. 2020 Nov 23;55(4):483-499.e7. Epub 2020 Sep 30. PubMed PMID: 33002421; PubMed Central PMCID: PMC7704111. [PDF]