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Chromatin Topology: the New (and Latest) Functional Complexity

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There’s a paper out in Nature Genetics discussing “chromatin topology.” Here’s the abstract:

A long-standing question in gene regulation is how remote enhancers communicate with their target promoters, and specifically how chromatin topology dynamically relates to gene activation. Here, we combine genome editing and multi-color live imaging to simultaneously visualize physical enhancer–promoter interaction and transcription at the single-cell level in Drosophila embryos. By examining transcriptional activation of a reporter by the endogenous even-skipped enhancers, which are located 150 kb away, we identify three distinct topological conformation states and measure their transition kinetics. We show that sustained proximity of the enhancer to its target is required for activation. Transcription in turn affects the three-dimensional topology as it enhances the temporal stability of the proximal conformation and is associated with further spatial compaction. Furthermore, the facilitated long-range activation results in transcriptional competition at the locus, causing corresponding developmental defects. Our approach offers quantitative insight into the spatial and temporal determinants of long-range gene regulation and their implications for cellular fates.

This is rather stunning stuff since what they are essentially saying is that the protein wrapping of DNA, the chromatin, is somehow functionally arranged, and that two distant sites on DNA (located 150,000 bases away from each other) NEED to come into contact for enhanced transcriptional activity. And, in the italicized section, they’re saying this comes about because the ‘needed’ conformation is somehow ‘stabilized,’ which means that the overall energy configuration of the local DNA molecule is lowered when put into this ‘conformation.’ (Oh how biochemists would love to be able to do such things!)

This only adds to the complexity of organisms to function properly and leaves in shambles the thought that all of these new layers of complexity came about by some “random” process.

I could post articles like this every day. I don’t because “News” does a good job of it, and over at Evolution and News, serious treatment of the more consequential articles routinely appear.

I cannot understand how any rational human being, aware of all this level of complexity, could possibly maintain a Darwinist, neo-Darwinist, or any other putative evolutionary (random) mechanism explains such orderliness and machine-like functioning.

We’re a long ways from thinking that ovum are just a bunch of goo. And yet . . . .

A related news item: Here.

Comments
UB, Maybe this paper relates to the tricky question you kept asking GC ? https://www.nature.com/articles/s41598-020-69100-0 :)jawa
December 8, 2020
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Did that guy ever respond to my question @240? Oh, well. Let’s get over it and move on. :) PS. I’m sure that UB realized that GC was a troll that somehow managed to leave the beautiful Norwegian fjords and couldn’t figure out how to get back to where he once belonged.jawa
December 8, 2020
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jawa, maybe someday he will.PaoloV
September 11, 2018
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Will George Castillo ever say something substantial that is worth reading?jawa
September 6, 2018
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Somebody fix that broken record! Ok, I'll play.George Castillo
September 1, 2018
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Join us, George.Upright BiPed
September 1, 2018
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That was your seventh time in this thread alone.Upright BiPed
August 30, 2018
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It's funny that you have to switch the word "evidence" to "material," upright. I guess it does actually suit you and your comedy act better.George Castillo
August 30, 2018
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you will continue to ignore any evidence that doesn’t support your worldview
Once again, allow me to repeat: ”Regardless of what anyone thinks preceded that time, at the point in earth’s history that the first ever aaRS was successfully synthesized from memory, how many of the other aaRS had to be in place?” When (or if) you return to tiptoe and dismiss the question once again, it will now be either the sixth or seventh instance on this thread alone where you've avoided material that doesn't support your worldview. Perhaps your zingers have lost all their sting.Upright BiPed
August 30, 2018
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You're "not interested" in this homology because it goes against your personal opinions. And yet you make numerous posts about the importance of homology... And based on the nature review, it's not just "one bacterial species" as you say, but actually Mycobacterium spp.; which refers to, I believe, well over 100 species of the genus Mycobacteria. But of course, no matter what I say, this example of homology is unimportant to you and you will just continue to ignore any evidence that doesn't support your worldview. I guess I really shouldn't be surprised. That's all.George Castillo
August 30, 2018
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George Castillo:
At no point did I argue that this bacterial NAP explains the existence of all eukaryotic histone sequences.
You can't even argue that it explains anything with respect to eukaryotes. You don't have a mechanism capable of producing eukaryotes given populations of prokaryotes and archaea. So that would be a problem, George
How do you propose HGT combined a bacterial histone-like protein with a segment of a eukaryotic histone?
Common design, not HGTET
August 30, 2018
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George Castillo: I have never said anything against "the importance of conserved homology", of course. Homology is always important. I don't want to demonstrate that HGT is the explanation for the observed homology. I simply don't know. But I think that nobody would seriouslky build and defend any evolutionary hypothesis based only on one observed homology of one sub-sequence in one protein of one bacterial species according to one old paper. Frankly, I am not so interested in this repetitive sequence found in mycobacterium tuberculosis and which has some homology with the C terminal domain of eukaryotic histone H1 family. Nor seems the scientific literature interested in it, or at least I am not aware of any follow-up to that observation. I am not even sure that the repetitive sequence is found only in that species, and not elsewhere in bacteria. I have no way to check that personally, because as explained that sequence eludes the blast algorithm. If someone will show that the sequence is well represented in bacteria, I will be happy to admit that it could be a reasonable ancestor for the eukaryotic C terminal domain of the histone H1 family (and only for that). Exactly as I have happily recognized, just from the beginning, that archaeal proteins could be reasonable ancestors of the eukaryotic histone fold, because the evidence for that was rather good. But in the absence of that kind of good evidence for bacterial sequences, I am not interested in hypotheses based on one single protein in one single species, and apparently lacking in all the rest of the bacterial world. That's all.gpuccio
August 30, 2018
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Peter, I agree with you. George Castillo still hasn’t addressed gpuccio’s main points in their discussion. Judging by George Castillo’s last comment, it doesn’t seem like he’s ready to continue this discussion. He should go back and read all gpuccio’s comments to see if he can finally understand the bottom line. Better, we all should accept gpuccio’s invitation to move to his new discussion thread.jawa
August 29, 2018
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gpuccio’s response @228 is very professional, totally acceptable and very clear. The ball is back in George Castillo’s court, which hasn’t responded previous comments.PeterA
August 29, 2018
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At no point did I argue that this bacterial NAP explains the existence of all eukaryotic histone sequences. Gpuccio, you have posted about the importance of conserved homology many times and yet here you brush it aside simply because it disagrees with your opinion. Do you really expect anyone to take you seriously when you do things like that? How do you propose HGT combined a bacterial histone-like protein with a segment of a eukaryotic histone?George Castillo
August 29, 2018
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George Castillo (and others): Excuse me for being late in answering, but I needed to make further research to understand well what was happening, and at the same time I was fully absorbed by my new OP (to which you are still invited to participate. So, to be really sure of the matter, I made further inquiries, and I found what follows: a) I was wrong about one thing. The N terminal domain you speak of is really a part of a specific histone protein, histone H1 (sometimes existing in a different form as histone H5). b) Histone H5 is not one of the gour histones that make the nucleosome strucure. However, it helps satbilize it, and has probably other roles, many of them still not understood. c) Differently from other histones, the H1 family is made of longer molecules, and it has a definite histone domain at the N terminal, and another repetitive sequence at the C terminal. That's exactly the sequence that aligns with the protein found in Mycobacterium tuberculosis. The bacterial protein, instead, has no significant alignment with the histone domain of the histone H1 family. d) So I apologize for my error: I believed that the C terminal sequence was some accessory sequence restricted to those 4 proteins, but that is not the case: it can be found in all H1 hostones C terminal sequences. e) Part of the reason for my error was that, strangely, the blast algorithm does not recognize and align that C terminal sequence in histone H1 proteins (and therefore not even in the mycobacteium tuberculosis protein). I have blasted many times different H1 histone one against the other, and no alignment is found for the C terminal sequence, while a hit is always shown for the histone domain at the N terminal sequence. I had to align the sequences with Mega to visualize the homologies in the C terminal sequence. I think that the reason for that is probably that it is a highly repetitive sequence, made of 4 AAs repetitions, and the blast algorithm has special rules for these "low informational" sequences. f) That said, I apologize again for the error. g) Error apart, what does that mean? h) It means that the protein in mycobacterium tubercolosis really has a detectable homology with a sequence found in the H1 family of eukaryotic histones, which is not the histone domain of the H1 family, and is not marked as a specific domain at Uniprot. i) However, as far as I can see, it has no homologies with the histone domain in the H1 family, or with the other histone families. j) The fact remains that that kind of homology does not qualify as an explanation for all the other basic histone sequences, domains and structures, which show no homology with the protein found in mycobacterium tuberculosis. k) The fact remains that, as far as I know and as far as can be understood by the papers you quoted, the protein in mycobacterium tuberculosis is an isolated case. Homologies or not, it does not qualify as a foundation for a credible ancestry of eukaryotic histones, because the best explanation for isolated cases remains, IMO, HGT. l) That said, I still cannot understand your insistence on a single finding in a single bacterial protein. As I have admitted just from the beginning that archeal proteins do show a structural similarity with eukaryotic histones, the only credible hypothesis is that eukaryotic histones may derive from archeal proteins, and not from bacterial ones that seem not to exist (whatever exception the mt protein may be). That's all. Just a final human note. It took you more than six days to answer my comments #194 and 195 (August 22 , 2 pm) with your comment #216 (August 28, 7.50 pm). Indeed, you never answered my #195. So, why were you taking offense that I needed some time (a few hours) to answer your last comments? "No response gpuccio?" Still invited to contribute to my new OP about transcription regulation. It is, indeed, an expansion of my comment #195 here.gpuccio
August 29, 2018
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Peter, Please, don't take a few statements or comments out of the context of their discussion. As far as I understand, the main point gpuccio is trying to make here is that the chromatin is functionally dynamic in vivo, which apparently is something that George Castillo strongly denied from the beginning of his discussion with gpuccio. Also I think gpuccio is trying to make the point that the functional complexity of the eukaryotic chromatin is designed, because it shows a tremendous jump in functional information anyway you look at it. A few similarities here and there don't make a dent in gpuccio's point. Not even a scratch. The issues George Castillo is trying to raise seem like digression from the main point to avoid it. Typical red herrings. Nothing new. We've seen this before here. Bikes, cars, trucks, buses, airplanes, trains, all have wheels. But there are major functional differences that were engineered (i.e. intelligently designed). Keep in mind the main point of the discussion lest you draw premature conclusions.jawa
August 29, 2018
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jawa, Don’t go so fast. Note that George Castillo has pointed to very specific problems in gpuccio’s affirmations. I think gpuccio should clarify this with more details. It’s human to err. He should admit any mistake in his statements, so that his credibility remains intact or even increases.PeterA
August 29, 2018
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No response gpuccio?
You might want to keep in mind that we live on a rotating planet.
Denying evidence, ignoring evidence
Allow me to repeat the question: ”Regardless of what anyone thinks preceded that time, at the point in earth’s history that the first ever aaRS was successfully synthesized from memory, how many of the other aaRS had to be in place?”Upright BiPed
August 29, 2018
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@220 gpuccio posed an interesting question that we have asked before. It took gpuccio much longer than me to ask such a question regarding the clueless and stubborn discussant he has dealt with so well. I’m sure other folks here (including myself) wouldn’t have kept that discussion that long.jawa
August 29, 2018
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George Castillo:
Bottom line is, there are bacterial proteins that are credible ancestors to histones
Oh my, you are dense. Just because the bacteria of today have it does not mean the ancient bacteria had it. Clearly you have no clue at allET
August 29, 2018
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No response gpuccio? Let me jog your memory, the 4 eukaryotic molecules with corresponding parts that align reasonably well with the NAP C-terminal domain are eukaryotic HISTONES. So when you say "the aligned sequence has nothing to do with histones" you are completely wrong. And when you deny that there are credible ancestors to histones in bacteria, you are also completely wrong. Denying evidence, ignoring evidence, and being flat out wrong...the UD trifecta!George Castillo
August 29, 2018
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What are the eukaryotic proteins that align reasonably well in figure 6?George Castillo
August 28, 2018
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George Castillo: Why am I wasting my time with you? You can't even understand English. Or you son't want to understand. In Fig. 6 of the paper, the C termoinal somain does align reasonably well with the corresponding parts of the 4 eukaryiotic molecules shown there. What a pity that the aligned sequence has nothing to do with histones! Good luck to you.gpuccio
August 28, 2018
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Oh boy. It's quite sad to watch you claim that a small amount of homology maintained over billions of years is meaningless, and then post about the importance of "jumps" of homology representing function because they've been maintained over millions of years. I guess that's what I should expect from UD. "Moreover, wherever did I “agree” that: 'the C-terminal segment displays homology to eukaryotic H1 histones'?" Let me refresh your dwindling memory; in comment 194 you said: "To make it brief, the alignments with a few eukaryotic histone molecules are in Fig. 6. The C terminal domain aligns reasonably well with the corresponding parts of the eukaryiotic molecules" At this point I'm questioning whether you even know what you're saying. Anyways, as I've said, there are credible bacterial ancestors to eukaryotic histones, at both the sequence and structural level. No obfuscation on your part will change that.George Castillo
August 28, 2018
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George, perhaps your situational awareness has failed you in this instance. To have any meaningful impact on GP's comments you'll have to actually address the details of what he says. That's usually how it works.Upright BiPed
August 28, 2018
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George Castillo: Don't embarass yourself any more. The fact that the C-terminal sequence of one bacterila protein has homology with 4 eukaryotic repetitive sequences found in 4 particolars eukaryotic proteins (and only in them) which are labeled as "histones" because a different part of the sequence has homology to the histone domain does not mean, in any possible way, that such homology of a repetitive sequence has anything to do with "being ancestor to histones". To be ancestor to histones, some bacterial protein should, of course, have homology to histone-specific sequences (the histone domain), or at least to histone specific structures (the histone fold). Even a child would understand that. Moreover, wherever did I "agree" that: "the C-terminal segment displays homology to eukaryotic H1 histones"? Read again my comment #194. I just quote that statment from the paper, and then I give very good evidence that it is not true. That's all. You are beyond any hope, you know? However, you are welcome to read, and if you like comment upon, my new OP about transcritpion regulation. After all, you contributed to motivate me to write it (sigh).gpuccio
August 28, 2018
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I'm glad that you agree that the "N-terminal exhibits significant homology to the bacterial HU proteins particularly in those amino acid residues implicated in DNA interaction, while its C-terminal segment displays homology to eukaryotic H1 histones," Gpuccio. That is also exactly what the original researchers found as I just quoted. It's unfortunate that you have to try to sweep this conserved homology under the rug in an effort to support your worldview, though. And just FYI, this bacterial protein was never claimed by anyone to have homology in the histone domain, it was at the N and C termini that there was homology to bacterial and eukaryotic proteins, respectively. You can check comment 185 again if you'd like. Maybe it is you who lacks careful attention, or maybe it's just a lack of knowledge in biology. Probably both. Bottom line is, there are bacterial proteins that are credible ancestors to histones They have similarites in structure and sequence that span the major kingdoms of life. This is true no matter how much you stomp your feet.George Castillo
August 28, 2018
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Friends: Maybe you have already seen that I have posted my new OP about these issues. You are warmly invited to the discussion! :)gpuccio
August 28, 2018
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Paolo, The repeated word reinforces its meaning. :) What about your opinion on the suggestion made by Eugene S? Do you support it?jawa
August 28, 2018
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