Jhamb D et al. (2011), Network based transcription factor analysis of ...

XB-ART-45099

BMC Bioinformatics 2011 Mar 18;12:80. doi: 10.1186/1471-2105-12-80.

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Network based transcription factor analysis of regenerating axolotl limbs.

Jhamb D , Rao N , Milner DJ , Song F , Cameron JA , Stocum DL , Palakal MJ .

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Studies on amphibian limb regeneration began in the early 1700's but we still do not completely understand the cellular and molecular events of this unique process. Understanding a complex biological process such as limb regeneration is more complicated than the knowledge of the individual genes or proteins involved. Here we followed a systems biology approach in an effort to construct the networks and pathways of protein interactions involved in formation of the accumulation blastema in regenerating axolotl limbs. We used the human orthologs of proteins previously identified by our research team as bait to identify the transcription factor (TF) pathways and networks that regulate blastema formation in amputated axolotl limbs. The five most connected factors, c-Myc, SP1, HNF4A, ESR1 and p53 regulate ~50% of the proteins in our data. Among these, c-Myc and SP1 regulate 36.2% of the proteins. c-Myc was the most highly connected TF (71 targets). Network analysis showed that TGF-β1 and fibronectin (FN) lead to the activation of these TFs. We found that other TFs known to be involved in epigenetic reprogramming, such as Klf4, Oct4, and Lin28 are also connected to c-Myc and SP1. Our study provides a systems biology approach to how different molecular entities inter-connect with each other during the formation of an accumulation blastema in regenerating axolotl limbs. This approach provides an in silico methodology to identify proteins that are not detected by experimental methods such as proteomics but are potentially important to blastema formation. We found that the TFs, c-Myc and SP1 and their target genes could potentially play a central role in limb regeneration. Systems biology has the potential to map out numerous other pathways that are crucial to blastema formation in regeneration-competent limbs, to compare these to the pathways that characterize regeneration-deficient limbs and finally, to identify stem cell markers in regeneration.

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Species referenced: Xenopus
Genes referenced: esr1 fn1 gsk3b hnf4a klf4 lin28a msx1 myc notch1 pou5f3 sox2 sp1 tp53

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References [+] :

Bachman, Duel nature of TGF-beta signaling: tumor suppressor vs. tumor promoter. 2005, Pubmed

	Figure 1. Venn diagram for a) upregulated and b) downregulated groups. The diagram shows the number of up and down regulated proteins in the axolotl proteomics data at 1, 4 and 7 day post amputation. 1d+ refers to the upregulated proteins and 1d- refers to the downregulated proteins at day 1. Other time points can be similarly interpreted. The value under each time point shows the total number of proteins up/down regulated at that time point.
	Figure 2. Transcription factor connectivity in axolotl proteomics data. The five most highly connected TFs (c-Myc, SP1, HNF4A, ESR1 and p53) and their downstream targets from the bait list proteins (represented by small green circles) are shown here. The size of the TF circle corresponds to its connectivity; a bigger circle entails higher overall connectivity. The targets in the outer circle are unique targets of each TF while those in the inner circle are shared by two or more TFs.
	Figure 3. c-Myc Network. The network shows c-Myc (enclosed by a black circle) with its 71 targets from the bait list. The horizontal lines separate the proteins in the network into the following categories: extracellular, membrane, cytoplasm, nucleus, and unspecified. The various symbols used in the network have been described in detail in the supplementary information [Additional file 7].
	Figure 4. SP1 Network. The network shows SP1 (enclosed by a black circle) with its 56 targets from the bait list.
	Figure 5. TGF-β1, SP1, FN network. The path from TGF-β1 to SP1 that ultimately leads to the activation of FN has been highlighted. The start point (TGF-β1) and end -point (FN) are highlighted with a circle and the connecting proteins are underlined.
	Figure 6. Fibronectin - c-Myc network. This network shows that multiple signaling pathways from FN can lead to the activation of c-Myc. The pathway highlighted in pink includes proteins involved in canonical Wnt signaling (GSK3beta, beta-catenin, and Tcf(Lef)).
	Figure 7. Stemness in limb regeneration. This network highlights the relationship of known stem cell markers (Oct3/4, Sox2, KLF4, Lin28) with TFs identified by this study (c-Myc and SP1) and previously identified TFs in limb regeneration (Msx1 and Notch1).