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From rectal cells to neurons : keys to understanding transdifferentiation

How can a specialized cell change its identity? A team from the Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/Université de Strasbourg) investigated a 100% effective natural example of this phenomenon, which is called transdifferentiation. This process, by which some cells lose their characteristics and acquire a new identity, could be more generally involved in tissue or organ regeneration in vertebrates, and is a promising research avenue for regenerative medicine. This study identifies the role of epigenetic factors involved in this conversion, underlines the dynamic nature of the process, and shows the key mechanisms for effective transdifferentiation. This work, conducted in collaboration with the Institut Curie1, was published on August 15, 2014 in Science.

How can a specialized cell change its identity? A team from the Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/Université de Strasbourg) investigated a 100% effective natural example of this phenomenon, which is called transdifferentiation. This process, by which some cells lose their characteristics and acquire a new identity, could be more generally involved in tissue or organ regeneration in vertebrates, and is a promising research avenue for regenerative medicine. This study identifies the role of epigenetic factors involved in this conversion, underlines the dynamic nature of the process, and shows the key mechanisms for effective transdifferentiation. This work, conducted in collaboration with the Institut Curie1, was published on August 15, 2014 in Science.

Our body is constituted of cells that acquired characteristics during development and that fulfill a precise function in each organ: we call these differentiated cells. Generally cells maintain their specificity until they die, but it has been proven that some cells can change state and acquire new functions. This is rare but is found in many species and is called “transdifferentiation”.

The team studied this process in C. elegans, a small transparent nematode, where a rectal cell transforms naturally into a motor neuron. This change from one cell type into another occurs without cell division, by a succession of well defined steps that always lead to the same result. The researchers investigated the factors that make the conversion process so stable.

The team had elucidated the role of several transcription factors2 in this transdifferentiation.

  But these new results have shown the role of so-called “epigenetic” factors that can modulate gene expression. Two protein complexes are involved in the mechanism. These enzymes act on a histone3 and when a mutation changes their action, the transdifferentiation stops and the rectal cell no longer transforms into a neuron.

The researchers observed that the two complexes act at different steps and that their role may change as a function of the transcription factors with which they are associated. These results underline the importance of the correct chain of steps for each of these molecules: the dynamic nature of the transdifferentiation mechanism is essential to its stability.

The respective role of genetic and epigenetic factors in biological processes is a hotly debated subject. This work shows how each of these factors acts in transdifferentiation: transcription factors handle initiation and progress whereas epigenetic factors guarantee the constant result. The study even goes further, showing that under “normal” conditions, the epigenetic factors are incidental (even when they are absent the conversion occurs relatively efficiently) but that they are indispensable when there are environmental stressors. So they have a crucial role in maximizing the mechanism’s efficacy and ensuring that it remains stable in the face of external variations.

Transdifferentiation is a phenomenon that is poorly understood. It may be involved in the organ regeneration that we observe in some organisms, for example newts, which can reconstruct their eye lens after injury. These results bring key new information to help us understand how to control this process and may open the path to promising therapies, in particular in the field of regenerative medicine.

image onion

© Elodie Legrand et Sophie Jarriault
We can compare this process to the layers of an onion. Transcription factors are at the heart of process efficiency, while epigenetic factors form the outer layers that protect the mechanism from attacks and environmental change.

(1) Unité Génétique et Biologie du Développement (CNRS/INSERM/Institut Curie)
(2) Proteins necessary for the DNA to RNA conversion
(3) Protein in the nucleus, around which the DNA rolls.

Lipids serving the brain

Consuming oils rich in polyunsaturated fatty acids, especially ‘omega 3’, is good for our health. But the mechanisms explaining these effects are poorly understood. Researchers from the Institute of Molecular and Cellular Pharmacology (CNRS/Nice Sophia Antipolis University), the Compartmentation and Cellular Dynamics Unit (CNRS/Curie Institute/UPMC) of Inserm and Poitiers University1 were interested in the effect of lipids carrying polyunsaturated chains when they are taken into cell membranes. Their study shows that the presence of these lipids makes them more malleable and thus much more sensitive to the action of proteins that deform and split them. These results, published in the journal Science on 8 August 2014, offer a route to explaining the extraordinary efficiency of endocytosis2 in neuronal cells.

Membrane plasmique en vert, transferrine en rouge

©Inserm/Barelli Hélène



The consumption of polyunsaturated fatty acids (such as ‘omega 3’ fatty acids) is beneficial for health. These effects go from neuronal differentiation to protection against cerebral ischemia3. However, the molecular mechanisms responsible for their effects are quite poorly understood. The researchers therefore looked into the role of these fatty acids in cell membrane function.

To ensure that a cell functions properly, its membrane must be able to deform and split up to form small vesicles. This phenomenon is called ‘endocytosis’. These vesicles generally allow cells to encapsulate molecules and transport them. For neurones, these synaptic vesicles perform the role of drive belt to the synapse for nerve impulses. They are formed inside the cell then move to its edge and merge with its membrane, in order to transfer the neurotransmitters that they contain. They are then reformed in less than one-tenth of a second: this is synaptic recycling.

In this work published in Science, the researchers showed that cellular or artificial membranes rich in polyunsaturated lipids are much more sensitive to the action of two proteins, dynamine and endophiline, which deform and split membranes. Other measurements from the study and simulations suggest that these lipids also make membranes more malleable. By facilitating the deformation and fission steps needed for endocytosis, the presence of polyunsaturated lipids could explain the speed of recycling for these synaptic vesicles.

The abundance of these lipids in the brain could therefore represent a major advantage for cognitive functions.

This work partially lifts the shroud covering the mode of action of omega 3s. Even if we know that our body cannot make them and that only suitable foods (rich in fish oil, etc.) provide them to us, it seems important to continue this work to understand the link between the functions these lipids perform in the neuronal membrane and their beneficial effects on health.

endocytose

Membranes containing monounsaturated lipids (left) and polyunsaturated lipids (right) after adding dynamine and endophiline. In a few seconds, the membranes rich in polyunsaturated lipids undergo multiple splits.© Mathieu Pinot

Transferrin endocytosis (iron transport) in cells containing polyunsaturated lipids in their membranes (right) compared to cells deprived of them (left). In 5 minutes, the number of endocytosis vesicles formed (internalised transferrin in red) is increased nearly 10 times, reflecting facilitated endocytosis.© Hélène Barelli

(1) This study was carried out in collaboration with teams from the Joint Applied Microscopy Centre (Nice Sophia Antipolis University) and the Signalling and Membrane Ionic Transport laboratory (CNRS/Poitiers University/Tours François Rabelais University).

(2) Endocytosis is the process by which cells absorb various substances present in the surrounding environment by encapsulating them in a lipoprotein membrane. It plays a role in various physiological functions.

(3) For example, see previous work by the Institute of Molecular and Cellular Pharmacology on this type of cerebro-vascular accident: Polyunsaturated fatty acids are potent neuroprotectors. Lauritzen I, Blondeau N, Heurteaux C, Widmann C, Romey G, Lazdunski M; EMBO J. (2000) 19:1784-93.

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