Choanoflagellates, singly and as a colony.
If there is one thing designed to get creationists chanting 'Common Designer!' it's evidence of the same gene doing the same thing in lots of different organisms, no matter how distantly related they are.
But when that gene is needed because of a basic design blunder long ago in the evolution of multicellular organisms, that chant looks increasingly forlorn.
For example, scientists have just shown how SOX and POU genes isolated from a single-celled choanoflagellate can be used to convert a mouse cell to function as the stem cell to clone another mouse. The reason this works is because something needs to reset the epigenetic setting in specialised cells. In a multicellular organism like a mouse, this effectively means any cell produced after the first few cell divisions of the fertilised zygote.
But why would a single-celled organism like a choanoflagellate need to do that? The answer it that epigenetics originally evolved to make an organism more able to respond to environmental changes and stresses.
What are choanoflagellates and why would a single-celled organism have Sox and POU genes which restore pluripotency in a cell from a multicellular organism such as a mouse? Choanoflagellates are single-celled eukaryotic organisms considered the closest living relatives of animals (metazoans). They have flagella surrounded by a collar of microvilli, which they use for feeding by capturing bacteria and other particles. As a bridge between unicellular and multicellular life, choanoflagellates provide insights into the evolutionary origins of multicellular animals.What this tells us then is that the complex system of epigenetics did not evolve anew with the first multicellular organisms, but is a coopted process evolved slowly over time to deal with two problems - transposons and the tendency of any environment to change over time.
Why would choanoflagellates have Sox and POU genes?
Sox (SRY-related HMG-box) and POU genes are transcription factors involved in regulating gene expression. These genes are crucial for maintaining or restoring pluripotency in multicellular organisms, such as in reprogramming mouse cells to an embryonic-like state. However, their presence in choanoflagellates, which are not multicellular, reflects their ancient evolutionary origins.
In summary, the presence of Sox and POU genes in choanoflagellates is a legacy of their shared evolutionary history with animals. These genes' roles in pluripotency and cell regulation in multicellular organisms represent an elaboration of ancient functions that first evolved in single-celled ancestors like choanoflagellates.
- Evolutionary Conservation:
- Sox and POU genes are deeply conserved across eukaryotes. Choanoflagellates, as close relatives of animals, inherited these genes from a common ancestor shared with multicellular animals. This common ancestor likely already used these genes for regulatory roles, perhaps in responding to environmental cues or in cell specialization processes.
- Functions in Choanoflagellates:
- In choanoflagellates, these genes may regulate functions related to cell cycle control, environmental responses, or differentiation-like processes. Although choanoflagellates are unicellular, they can exhibit colony formation, which requires coordination and signalling akin to multicellular organization.
- These genes could also regulate developmental plasticity, enabling choanoflagellates to adapt to changing environments by switching between different forms or behaviours.
- Role in Multicellular Evolution:
- The functions of Sox and POU genes in choanoflagellates might have been co-opted during the evolution of multicellular organisms for roles in stem cell maintenance and differentiation. These genes were likely involved in early regulatory networks that laid the groundwork for multicellularity.
Why is epigenetics required in single-celled organisms not just multicellular organisms?
While epigenetics is particularly crucial in multicellular organisms for coordinating cell differentiation and maintaining tissue-specific gene expression, it also plays important roles in unicellular organisms. Here's why:
Epigenetics in Multicellular Organisms
In multicellular organisms, epigenetics ensures that cells with the same DNA can differentiate into specialized types (e.g., muscle, neurons, skin) and maintain their identity over time. Examples include:These mechanisms allow for the stable inheritance of gene expression patterns without altering the DNA sequence, which is essential for development and homeostasis.
- DNA methylation: Silencing genes in cells where they shouldn't be active.
- Histone modifications: Packaging DNA to regulate gene accessibility.
- Non-coding RNAs: Modulating gene expression post-transcriptionally.
Epigenetics in Unicellular Organisms
Even single-celled organisms benefit from epigenetic regulation. Here's how:
- Environmental Adaptation:
- Gene regulation: Epigenetic changes can help unicellular organisms rapidly adapt to environmental conditions, such as nutrient availability, temperature, or stress.
- Example: Bacteria and yeasts can use DNA methylation or histone-like modifications to regulate genes critical for survival under varying conditions.
- Phenotypic Plasticity:
- Some unicellular organisms exhibit phenotypic switching (e.g., pathogenic fungi switching between yeast and filamentous forms). These transitions are often regulated by epigenetic mechanisms.
- Cell Memory:
- Epigenetic marks can serve as a "memory" of past environmental conditions, influencing future responses. For instance, certain stress responses in yeasts and other microbes depend on chromatin changes that persist through generations.
- Transposon Control:
- Like in multicellular organisms, unicellular organisms must suppress transposable elements (jumping genes) that could disrupt their genomes. Epigenetic silencing mechanisms such as small RNAs and DNA methylation play a role here.
Origins and Evolutionary Perspective
Epigenetic mechanisms likely evolved before multicellularity, enabling early single-celled organisms to regulate gene expression dynamically. These mechanisms were later co-opted and elaborated upon in multicellular organisms to support the complexity of cell differentiation and tissue specialization.
Conclusion
Epigenetics is not exclusive to multicellular organisms; it also serves critical regulatory functions in unicellular life. Its universality highlights its evolutionary importance for all forms of life, both simple and complex.
Normally we would expect a Discovery Institute fellow like Michael J. Behe or William A. Dembski, to declare this system is so complex it must have been made by magic and rush out another book using the false dichotomy fallacy to force-fit their god into another manufactured gap - and make another few million dollars with a book widely acclaimed by scientifically illiterate theologians and condemned by professional biologists as fraudulent.
One of the problems of epigenetics that apparently had already been solved by the ancestors of both choanoflagellates and multicellular animals was the need to reset the whole thin and start again in a new cell, and this is what the SOX and POU genes did. So important is this to eukaryote organisms that it has been highly conserved during the hundreds of millions of years that animal life has been evolving, so can still be used to restore pleuripotency in a mouse cell, so it has the full potential to develop into any specialised mouse cell, as Dr Alex de Mendoza of Queen Mary University of London collaborated with researchers from The University of Hong Kong discovered.
Scientists recreate mouse from gene older than animal life
New research sheds light on evolutionary origins of stem cells with groundbreaking experiment to create mouse using ancient genetic tools
Published in Nature Communications, an international team of researchers has achieved an unprecedented milestone: the creation of mouse stem cells capable of generating a fully developed mouse using genetic tools from a unicellular organism, with which we share a common ancestor that predates animals. This breakthrough reshapes our understanding of the genetic origins of stem cells, offering a new perspective on the evolutionary ties between animals and their ancient single-celled relatives.
In an experiment that sounds like science fiction, Dr Alex de Mendoza of Queen Mary University of London collaborated with researchers from The University of Hong Kong to use a gene found in choanoflagellates, a single-celled organism related to animals, to create stem cells which they then used to give rise to a living, breathing mouse. Choanoflagellates are the closest living relatives of animals, and their genomes contain versions of the genes Sox and POU, known for driving pluripotency — the cellular potential to develop into any cell type — within mammalian stem cells. This unexpected discovery challenges a longstanding belief that these genes evolved exclusively within animals.
The mouse on the left is a chimeric with dark eyes and patches of black fur, a result of stem cells derived from a choanoflagellate Sox gene. The wildtype mouse on the right has red eyes and all white fur. The colour difference is due to genetic markers used to distinguish the stem cells, not a direct effect of the gene itself.Credit: Gao Ya and Alvin Kin Shing Lee
Centre for Comparative Medicine Research (CCMR).By successfully creating a mouse using molecular tools derived from our single-celled relatives, we’re witnessing an extraordinary continuity of function across nearly a billion years of evolution. The study implies that key genes involved in stem cell formation might have originated far earlier than the stem cells themselves, perhaps helping pave the way for the multicellular life we see today.
Dr. Alex de Mendoza, co-lead author.
School of Biological and Behavioural Sciences
Queen Mary University of London, London, UK.
The 2012 Nobel prize to Shinya Yamanaka demonstrated that it is possible to obtain stem cells from “differentiated” cells just by expressing four factors, including a Sox (Sox2) and a POU (Oct4) gene. In this new research, through a set of experiments conducted in collaboration with Dr Ralf Jauch’s lab in The University of Hong Kong / Centre for Translational Stem Cell Biology, the team introduced choanoflagellate Sox genes into mouse cells, replacing the native Sox2 gene achieving reprogramming towards the pluripotent stem cell state. To validate the efficacy of these reprogrammed cells, they were injected into a developing mouse embryo. The resulting chimeric mouse displayed physical traits from both the donor embryo and the lab induced stem cells, such as black fur patches and dark eyes, confirming that these ancient genes played a crucial role in making stem cells compatible with the animal’s development.
The study traces how early versions of Sox and POU proteins, which bind DNA and regulate other genes, were used by unicellular ancestors for functions that would later become integral to stem cell formation and animal development.
Choanoflagellates don’t have stem cells, they’re single-celled organisms, but they have these genes, likely to control basic cellular processes that multicellular animals probably later repurposed for building complex bodies.
Dr. Alex de Mendoza.
This novel insight emphasises the evolutionary versatility of genetic tools and offers a glimpse into how early life forms might have harnessed similar mechanisms to drive cellular specialisation, long before true multicellular organisms came into being, and into the importance of recycling in evolution.
This discovery has implications beyond evolutionary biology, potentially informing new advances in regenerative medicine. By deepening our understanding of how stem cell machinery evolved, scientists may identify new ways to optimise stem cell therapies and improve cell reprogramming techniques for treating diseases or repairing damaged tissue.
Studying the ancient roots of these genetic tools lets us innovate with a clearer view of how pluripotency mechanisms can be tweaked or optimised.
Dr Ralf Jauch, co-lead author
School of Biomedical Sciences
Li Ka Shing Faculty of Medicine
The University of Hong Kong, Hong Kong SAR, China.
[Dr Jaunch noted] that advancements could arise from experimenting with synthetic versions of these genes that might perform even better than native animal genes in certain contexts.
AbstractWhat creationists might prefer to ignore here is not only that the scientists were in no doubt about the evolutionary origins of the epigenetic system, but, by using the Theory of Evolution, they knew where to find the SOX and POU genes, not in an ancestor of mice, or mammals, or even in vertebrates, but in the ancestor of all multicellular eukaryote animals, a single-celled choanoflagellate a close relative of the ancestor of all the animals.
Stem cells are a hallmark of animal multicellularity. Sox and POU transcription factors are associated with stemness and were believed to be animal innovations, reported absent in their unicellular relatives. Here we describe unicellular Sox and POU factors. Choanoflagellate and filasterean Sox proteins have DNA-binding specificity similar to mammalian Sox2. Choanoflagellate—but not filasterean—Sox can replace Sox2 to reprogram mouse somatic cells into induced pluripotent stem cells (iPSCs) through interacting with the mouse POU member Oct4. In contrast, choanoflagellate POU has a distinct DNA-binding profile and cannot generate iPSCs. Ancestrally reconstructed Sox proteins indicate that iPSC formation capacity is pervasive among resurrected sequences, thus loss of Sox2-like properties fostered Sox family subfunctionalization. Our findings imply that the evolution of animal stem cells might have involved the exaptation of a pre-existing set of transcription factors, where pre-animal Sox was biochemically similar to extant Sox, whilst POU factors required evolutionary innovations.
Introduction
The evolution of animal multicellularity around 700 million years ago was a key step that shaped all aspects of our planetary history. As multicellular entities, most animals including early branching sponges harbor pluripotent stem cells1. Stem cells can indefinitely produce identical copies of themselves or, upon stimulation, can form all the specialized cell types of an organism. Stem cells that can become any somatic cell type are known as pluripotent stem cells, whereas multipotent stem cells are lineage-restricted only giving rise to certain cell types. For example, neural stem cells can differentiate into neurons, astrocytes and oligodendrocytes. In vertebrates, pluripotent stem cells only transiently exist during the early stages of embryo development and are characterized by the expression of a core set of transcription factors (TFs) that induce and maintain stemness. Among these TFs, the Sry-related box 2 (Sox2) and octamer-binding transcription factor 4 (Oct4) are key pluripotency factors that need to be present and active at tightly regulated levels. Their removal or subtle perturbances to their abundance lead to the loss of self-renewal and pluripotency2,3. Sox2, Oct4, and other factors have been described as “Pioneer” TFs, capable of binding their target motifs even in closed chromatin and to DNA wrapped around a nucleosome4,5,6,7. Pioneering TFs are critical to direct cell fate transitions during embryonic development including the zygotic genome activation that precedes the formation of pluripotent stem cells8,9,10,11. To open up chromatin and regulate genes, Sox2 and all other Sox family members encode a conserved 79-amino-acid-long high mobility group (HMG) box domain that mediates sequence-specific binding to and bending at CATTGT-like DNA sequences12,13.
Previous phylogenetic reconstructions showed that the Sox clade lacked any reliable non-metazoan HMG box sequences. Therefore, Sox genes were considered a unique animal-specific sub-family within the broader HMG class14,15,16,17,18. At the onset of metazoan radiation, Sox genes expanded into five major paralogous families: SoxB-F19. As cnidarians, sponges and placozoans harbor neurogenic, pluripotent or peptidergic stem cell populations that express Sox2 orthologues (SoxB group members), likely, the association of SoxB genes with stemness evolved early in animals20,21,22,23. Given that stem cells across animals might not be homologous, it is also possible that SoxB members possess biochemical features that make them more likely to be convergently deployed in stem cell regulation across lineages. The level of functional conservation of Sox members across different animal lineages is currently not well understood.
The role of Sox2 in mammalian pluripotent stem cells is tied to its ability to form DNA-dependent heterodimers with Pit-Oct-Unc (POU) family factors such as Oct45,13,24,25,26. The degree of Sox2/Oct4 cooperativity is key for pioneer binding in naïve epiblast cells of day 4.5 mouse embryos27 and determines the quality and developmental potential of pluripotent stem cells across mammalian species28. The heterodimerization between Sox2 and Oct4 is also essential for the generation of induced pluripotent stem cells (iPSCs) during somatic cell reprogramming conventionally driven by the four-factor Yamanaka cocktail Sox2, Oct4, Klf4 and c-Myc29. Only Sox2 and other SoxB members can induce pluripotency in vertebrates as part of this cocktail, whilst Sox factors from the SoxC, D, E and F families cannot30,31,32. If the Sox2/Oct4 partnership is disrupted with mutations, iPSC generation fails25,33,34,35. POU factors are characterized by the presence of a POU-specific domain and a POU homeodomain connected by a flexible linker that jointly bind the ATGCAAAT sequence (known as the Octamer)13. POU factors form six families (POU1, 2, 3, 4, 5 and 6), where POU5/Oct4 is a vertebrate-specific duplication of a POU3 member36. POU factors were also assumed to be an animal-specific invention14,17,36,37,38,39,40,41.
In this work, we re-examine the evolutionary origins of Sox and POU transcription factors by focusing on unicellular relatives of animals. We find orthologs of these transcription factors in previously uncharted choanoflagellates and filastereans. Since these species are unicellular, they do not form stem cells. We show that choanoflagellate Sox is capable of inducing pluripotency in mouse somatic cells. In contrast, choanoflagellate POU binds DNA motifs distinct from animal homologs and cannot induce pluripotency. We propose that the Sox/POU partnership could have emerged early during animal evolution and was likely driven via molecular exaptation of the previously established Sox-POU-DNA dimerization and binding capacities. Our findings foster our understanding of the molecular evolution of Sox/POU, which we hypothesize could have been critical for the advent of stem cells and animal multicellularity.
Chimeric mice generated from full-length Salhel-Sox-I iPSC lines displaying black coat patches and eyes (indicated by arrows) representing their iPSC origin, in contrast to the wildtype mouse exhibiting a white coat and red eyes.Gao, Y., Tan, D.S., Girbig, M. et al.
The emergence of Sox and POU transcription factors predates the origins of animal stem cells Nat Commun 15, 9868 (2024). https://doi.org/10.1038/s41467-024-54152-x
Copyright: © 2024 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
The other thing creationists might like to ignore is how the epigenetic system evolved for a different purpose and was exapted for its current purpose in multicellular organisms in the same way other 'irreducibly complex' systems are.
Refuting Creationism: Why Creationism Fails In Both Its Science And Its Theology
A systematic refutation of creationism, exposing the childish parodies, fallacies and pseudo-science that underpins it. This book takes the reader through the major themes of creationism from the Big Bang, through abiogenesis and the origin of the genetic code, the evidence for evolution, falsifying the claims of creationism with scientific evidence. Also exposed is the deliberate disinformation to be found on creationist websites and publications and the absurdity of the belief that the Bible, particularly the origin myths in Genesis, is real science and genuine history, written or inspired by an omniscient, inerrant creator god
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The Failure of Creationism: The Theory That Never Was
An exposé of the failure of creationism and especially the Discovery Institute's Wedge Strategy, showing that the Theory of Evolution is as central to biomedical science today as it was when the DI launched its disinformation campaign in 1991. Creationism is not a science; it is religious fundamentalism and, as was shown in the Kitzmiller case, Intelligent design is creationism dressed in a lab coat.
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