Immediate early response
Overview and background
The purpose of this page is to address the most significant biological questions that might be asked of the time course analyses as they relate to the immediate early response (IER). We hope that this will direct some of the critical analyses of the IER and so inform this aspect of the time course main paper.
Important considerations for discussion:
What are the biggest knowledge gaps in IER biology that might be addressed with the F5 timecourse data?
What are the primary punchlines that we can provide to the main paper?
IER may be an essential component of cell-state transitions.
Kim's data may suggest that IER is necessary BUT NOT SUFFICIENT for cellular differentiation.
Mariko's data may also suggest that an early responsive gene network actually functions to drive cell fate specifically:
Amplitude and duration of upstream signal define IER gene activity (Signal-dependent)
and also
microRNA levels define IER gene expression (miRNA-dependent) - for confirmation.
What are the core analyses required across the timecourses? Which timecourses should be included in an analysis of IER?
Extracted from the presentations below: 1. What is comparative time course of Egr-1 or c-Jun-dependent gene expression across different samples/stimuli? Do differences in onset, duration or amplitude reflect differences in the biology (e.g. Fgf vs IL1B activation of SMC or EGF/HRG stimulation of MCF7)
2. Can we expand the set of IER genes: Which genes correlate closely with the known IER genes (in particular Egr-1)? How does this vary across activation vs differentiation type stimuli? Do we expect to see the same genes, or should we expect to see the same functional categories (different gene, similar purpose).
3. Can we identify features of enhancer/promoters associated with IER genes, or targets of IER transcription factors?
4. Do all cells transition or undergo changes in gene expression, or is this more a process of comparatively few cells?
5. Should we expect to see an IER only at the start of a timecourse? If several transitional states are moved through (eg a series of developmental stages) then might the IER be necessary to tip the transition points? Can the later timecourses (or in vivo timecourses of Thomas') help address this question?
6. The IER is self-limiting. (can we see chromatin evidence of how, and when?) Does this reset once all cells have transitioned?
In the time course meeting (Oct 2012), there were several presentations on the topic of immediate early response. They are available at the time course meeting page but also linked here for convenience:
- Christine Wells introduction File:FANTOM time course CW.pdf
- "Early responsive genes in MCF-7 breast cancer cells" - (Mariko Okada) File:FANTOM Early gene 2012-short Okada.pdf
- "Neuronal type specification and Transcription factors in cerebellar development" - (Thomas Ha) File:TH TFs in cerebellum development 121029.pdf
- "Early Time Point AnalysisSAOS2 calcification" - (Kim Summers) File:Time points KMS.pdf
- "Early response analysis" - (Erik Arner) File:Timecourse meeting ier 20121030.pptx
- ""Immediate-early genes as regulators in cancer and vascular disease"" - (Levon Khachigian) File:Levon FANTOM5-1.pdf
IER gene lists
Mariko Okada has provided gene lists derived from the literature.
- This is on MCF-7 cells, but it will be useful to start from here.
- File:Genelist-2006-01-16-with-fc2.xls
- Analysis of this paper is described here;
- A similar work has been also done by Eric Lander;
- Additional info on IEG in rat PC12 stimulated with NGF (a sustained signal inducer, relevant to HRG in MCF-7).
