CREB-binding protein (CBP) gene family regulates planarian survival and stem cell differentiation

Abstract

The regulation of stem cells plasticity and differentiation is still an open question in developmental biology. CBP (CREB-binding protein)/p300 is a conserved gene family which functions as a transcriptional co-activator and shows an important role in a wide range of cellular processes, such as cell death, DNA damage response and tumorigenesis. Moreover, CBPs have an acetyl transferase activity that is relevant as histone and non-histone acetylation results in changes in chromatin architecture and protein activity that affects gene expression. Many studies have shown the conserved functions of CBP/p300 on stem cell proliferation and differentiation. The planarian Schmidtea mediterranea is an excellent model to study in vivo the molecular mechanism underlying stem cell differentiation during regeneration. We have identified five different Smed-cbp genes in S. mediterranea that show different expression patterns. Functional analyses indicate that Smed-cbp-2 seems to be essential for stem cell maintenance and cell survival. On the other hand, the silencing of Smed-cbp-3 results in the growth of apparently normal blastemas; however, these remain largely depigmented and undifferentiated. Smed-cbp-3 silencing affects the differentiation of several cell lineages including neural, epidermal, digestive and excretory cell types. Finally, we have analyzed the predicted interactomes of CBP-2 and CBP-3 as an initial step to better understand their function on planarian stem cell biology.

Intestine-enrichedapolipoprotein borthologs are required for stem cell differentiation and regeneration in planarians

“…In planarians, specification likely begins during S-phase, because expression of fate-specific transcription factors is significantly higher in S/G2/M neoblasts than in G1 neoblasts 57,62 . Intriguingly, inhibition of other planarian genes required for differentiation (e.g., the transcription factor mex3-1, the extracellular matrix component collagen4-1, and the transcriptional co-activating protein cbp-3) also cause increases in neoblast numbers in vivo 52,[63][64][65] . Furthermore, knockdown of exocyst component 3 (exoc3), a negative regulator of pluripotency whose mammalian homolog Tnfaip3 promotes embryonic stem cell differentiation, causes expansion of the S/G2/M (X1) neoblast fraction 66 .…”

“…Because acetyl-CoA can also enter the citric acid cycle to produce alpha-ketoglutarate, a substrate for histone demethylation 71 , ApoB inhibition could dysregulate epigenetic changes through multiple pathways. Histone acetylases, deacetylases, methyltransferases, and demethylases are conserved in planarians, and their inhibition disrupts stem cell maintenance, differentiation, and regeneration 64,65,[72][73][74][75] . Because apob RNAi results in widespread dysregulation of thousands of transcripts associated with differentiating progeny, it is reasonable to suggest that in planarians, intestinal lipid stores serve as a ready carbon source that is trafficked by ApoB-containing LPs to neoblasts and progeny to support epigenetic modifications required for differentiation.…”

Decoding Stem Cells: An Overview on Planarian Stem Cell Heterogeneity and Lineage Progression

“…Recently, two different studies have uncovered the function of the planarian CREBbinding protein (CBP)/p300 family in neoblast biology [126,140]. These transcriptional co-activators play different roles either by acetylating both histone and non-histone proteins (i.e., transcription factors) or serving as protein scaffolds [141][142][143].…”

“…These transcriptional co-activators play different roles either by acetylating both histone and non-histone proteins (i.e., transcription factors) or serving as protein scaffolds [141][142][143]. On one hand, cbp-2 appears to be required for stem cell maintenance and planarian survival, as after its silencing, the animals show a significant reduction in the number of neoblasts and proliferative cells and die after a few days of treatment [126,140]. On the other side, cbp-3 appears to be mainly involved in neoblast differentiation, although some differences are reported in both studies that might be explained by the different RNAi experimental set up as well as the long-term effects of its silencing.…”

“…Most invertebrates have just one CBP homologue, and a duplication at the base of the vertebrate lineage seems to be the origin of the p300 gene in that phylum [144]. Remarkably, S. mediterranea possess five CBP homologues as a consequence of possible duplication events specific to the phylum Platyhelminthes [126,140]. Even though vertebrates CBP and p300 interact with mainly the same proteins, their functions are not completely redundant [144].…”