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Skip to 0 minutes and 27 secondsToday we are going to talk on the regulation of the genome, the genome in action; what really matters. And we have with us Miguel Beato. Miguel Beato is group leader in the CRG working on chromatin and gene expression. He’s a very well-known biologist; he’s been one of the leading scientists in Europe, he has done most of his career in Germany, and then in 2001 moved to Barcelona where he has been the creator and director of the Center for Genome Regulation, a very successful center.

Skip to 1 minute and 2 secondsHe has been very interested in the regulation of the genome, that is, how genes are expressed, how genes really enter in action and how hormones and other factors… did really have matter in this regulation and in making the genome to be what really is the genome in action. One of the key points now is the understanding of the external factors and the packaging of this genome. Thank you very much, Miguel Beato. Every individual has a single, the same genome in all our cells. What makes the difference among cells, among tissues? Well I must say that it’s becoming clear that not all our cells have the same genome.

Skip to 1 minute and 53 secondsAs sequencing of more tissues and cell types is becoming available, it’s clear that somatic cells have mutations and different genomes and amplifications, all kind of little changes. Of course some of these cells are completely different in the immune system as well. But in general, it’s true that the genome is basically one genome, and we normally operate with this assumption. Nevertheless, what makes the difference is actually the way the genome is packaged in the cell nucleus. So there… we would not be here if the genome was not organized in chromatin, which is wrapped around nucleosomes and folded in a complicated way.

Skip to 2 minutes and 44 secondsAnd at several levels, the nucleosome is the first, folding, and the fiber of nucleosome is another one, and the fiber makes loops, and the loops make domains, and the domains make chromosomes, and so on. So it’s a very complicated structure that actually appeared in evolution because it was necessary to prevent the repulsion among the negative charges of the phosphates in the DNA. So they wrap around these cylinders of histones that actually have all in the surface positive charge that neutralize the charge so you can pack the genome very tightly.

Skip to 3 minutes and 26 secondsSo this is the prerequisite for having complex genomes, but this needed also to create a cell nucleus which is an organelle that deals with the dynamics of the genome; the replication, the expression. This is actually the brain of the cell. And so, the way the genome is packed in the somatic cells of our organism, different tissues, is different. It’s different, the way in which the folding in chromatin takes place, and the way how the fiber of chromatin forms the loops and domains. So there are several levels in which each cell has a separate way of folding the genome. And it’s kind of the same metaphor of origami.

Skip to 4 minutes and 25 secondsSo you can take the same piece of paper and fold it in different ways to make a house or a boat or, you know, a fish, whatever. You can make all kind of things that have different form. And I think the most important conceptual advance is to understand that the form of the genome is essential. Not the sequence of nucleotides, but the form, and the form is given by chromatin and folding and so on. So the form at the very end will drive the action, the function of the genome. Exactly. And it’s very curious that in Roman language, “information” includes “form”. It’s actually kind of an intuition that the form, the structure, is functional information.

Skip to 5 minutes and 21 secondsBut in the regulation, there are factors, internal and external, that do matter for using different parts of the genome. You’re right. I mean, in development, the folding of the genome is a cascade of events that happens in cell division, in the embryo which has relatively little organization – although we will come back to this, there is organization already in the egg. When asymmetric cell divisions lead to asymmetric distribution of transcription factors, and these transcription factors - this is a very new concept - are not only responsible for the expression of a specific part of the genome, but those are for the genome in a particular way, because they are a structural component of the chromatin.

Skip to 6 minutes and 16 secondsAnd so, these transcription factors are key players, but the form they impose in the genome is essential for the next transcription factor that comes to operate properly. So it’s two kinds of processes, binding of the transcription factor and folding of the genome that actually decide how at the end the genome will be formed in the liver cell or in the skin or in the retina in very different ways. So this explains why the genes are expressed in different ways. And this happens at a very, very small scale. Yes, I mean, well there are all kind of signals that keeps that going, it’s not a crystallized genome; it’s dynamic, it’s continually moving and maintained in a particular conformation. This needs energy.

Skip to 7 minutes and 16 secondsBut we usually say that when we speak about the several-meter genome of humans, for instance, it’s almost 2 meters packed into a cell nucleus that has a diameter of 8 or 10 microns. So, compact but it’s very thin. In fact if you look carefully with modern high-resolution techniques in the nuclei, there is a lot of space free. So a lot of space for things to happen despite these 2 meters packed very tightly. Really it has been solved in a very engineering, fantastic way, structure of the DNA. Yes.

Skip to 8 minutes and 8 secondsThe interesting challenge that we have now to combine modern ways of sequencing, knowing the sequence, techniques that allow to see the folding, and microscopy that allows to see individual cells in movement, live microscopy to see how things are. But in the last years we have heard many times the word “epigenomics” in such a way that seems that epigenome would explain many things that the genome by itself could not. What is an epigenome and why does it matters? Well, from Aristotle, there is a long tradition that has meant very different things. It was development, essentially, at the beginning. But now the concept has been enriched and enriched with new discoveries.

Skip to 8 minutes and 59 secondsEssentially, the chromatin; essentially the way the chromatin contributes to shaping the form of the genome. But also the changes in the sequence and the modifications of the bases that form the genome, methylation, hydroximethylation there are more and more modifications that are becoming available. This part of the epigenetic…because the sequence is the same, but it can be modulated by modifying the bases or by millions of different combinations, modifications, of histones.

Skip to 9 minutes and 37 secondsThe histones that form these cylinders which the DNA is wrapped around, they have protruding ends that are like antennas that send signals from the cells - usually kinases or phosphatases - and change the combination of modifications in a way that is still not completely known, but that determines how the fiber folds. And this is fascinating, this is modern epigenetics. Indeed. So we have the sequence of the DNA, we have the epigenome, we have this very complex 3D structure. Of all of that, what is transmitted among generations? Well this is not completely clear. Until recently we thought it was just the DNA with a few modifications or something.

Skip to 10 minutes and 31 secondsBut it’s becoming clear that even in the oocyte and in the sperm, there are already histone marks on the DNA. So not only are there methylation marks that are maintained - most of them RNAs but others are maintained - but modifications of the histones, particularly methylation of histones that are already there in the size that will be important for the embryonal stem cells. So this is a very novel finding that is quite surprising. And then more and more RNAs are transmitted as well. There are RNAs that are associated with the chromatin, part of the epigenome, if you want, those are transmitted.

Skip to 11 minutes and 24 secondsBut it seems that this transmission will last just a few generations. This cannot be something essential for evolution. It’s true.

Skip to 11 minutes and 31 secondsI mean there are two transmissions: the one that happens during transgenerational inheritance, from the fathers to the descendants. This is still not very well understood. But the one that happens when a cell divides, it has to transmit all this information. It was thought that during mitosis, when the cell divides, the nuclear membrane is lost, the chromatin loses its organization, all the factors detach from the DNA. Nevertheless, within a few minutes, it’s reconstructed. So now we know the idea that the factors are not attached during mitosis wasn’t out of the fact of the technology for the fixations. You change that, many factors remain bookmarking certain positions, and modification of the systems are inherited in mitosis.

Skip to 12 minutes and 32 secondsSo it’s relatively easy once the cells have divided to reconstruct

Skip to 12 minutes and 38 secondsthe new chromatin - newly synthesized - and the old chromatin reconstructed: the epigenetic identity. Through generations is a little bit more complicated. But one of the most important papers was just published very recently by Ben Lehner in C. elegans. A little perturbation with heating, a little bit of heating, a few degrees, over the temperature that is normal for the C. elegans generated epigenetic change that is inherited in 14 generations. So this is quite surprising, just a small perturbation in the temperature. So I think there is much more to be learned about what is inherited. Methylation of lysine 9 is inherited, methylation of lysine 4 is inherited… I don’t know.

Skip to 13 minutes and 37 secondsWe give to our kids more than just the sequence of DNA. So you have seen that we are at the edge of research in the regulation of the genome and mainly in understanding the 3D structure of this DNA when it enters in action. Thank you very much, Miguel.

Conversation with Miguel Beato

Miguel Beato, Group leader on Chromatin and Gene Expression at the CRG, Barcelona.

Miguel Beato has been interested in the regulation of the genome, that is, how genes are expressed or repressed by hormones and how the spatial structure of the DNA packaging is fundamental for understanding the genome at action.

Important concepts from the video

1. Chromatin (2.30)

A complex of macromolecules consisting of DNA, protein (mainly histones) and RNA that is the way DNA is packed to make chromosomes. The primary functions of chromatin are 1) to package DNA into a more compact, denser shape, 2) to reinforce the DNA macromolecule to allow mitosis, 3) to prevent DNA damage, and 4) to control gene expression and DNA replication.

2. Nucleosome (2.35)

A nucleosome is a basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound in sequence around eight histone protein cores.


3. Transcription factor (5.55)

A protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. Their function is to regulate – turn on and off – genes in order to make sure that they are expressed in the right cell at the right time and in the right amount throughout the life of the cell and the organism.

4. Epigenomics (8.30)

The study, in the whole genome, of the epigenetic modifications, which are reversible modifications on a cell’s DNA or histones that affect gene expression without altering the DNA sequence.

5. Metilation (9.13)

One of the main epigenetic modifications, DNA methylation is a process by which methyl groups are added to the DNA molecule, changing the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription.

6. Histones (9.30).

Histones are proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes (see nucleosome, in this list). They are the chief protein components of chromatin, acting as spools around which DNA winds, and playing a role in gene regulation.

7. Kinase (9.45)

In biochemistry, a kinase is an enzyme that catalyzes a process called phosphorylation, the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. The phosphorylation state of a molecule, whether it be a protein, lipid, or carbohydrate, can affect its activity, reactivity, and its ability to bind other molecules. Therefore, kinases are critical in metabolism, cell signaling, protein regulation, cellular transport, secretory processes, and many other cellular pathways, which make them very important to human physiology.

8. Embryonic stem cells (10.58)

Embryonic stem (ES) cells are the cells of the inner cell mass of a blastocyst, an early-stage embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells. ES cells are pluripotent and give rise during development and they can develop into each of the more than 200 cell types of the adult body when given sufficient and necessary stimulation for a specific cell type.

9. C. elegans (12.50)

Short name for Caenorhabditis elegans, a free-living (not parasitic), transparent nematode (roundworm), about 1mm in length, that lives in temperate soil environments. It is being used as a model organism for biology and is one of the best known species at the molecular and cellular level.


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Why Biology Matters: Basic Concepts

Pompeu Fabra University Barcelona