内容来源：https://www.quantamagazine.org/loops-of-dna-equipped-ancient-life-to-become-complex-20251008/

内容总结：

【科技讯息】一项发表于《自然》杂志的最新研究揭示，动物从简单生命演化为复杂形态的关键可能在于DNA的"环状结构"。由巴塞罗那基因组调控中心的阿尔瑙·塞贝-佩德罗斯带领的科研团队发现，远古海洋生物通过形成染色质环，实现了基因调控机制的突破性进化。

研究聚焦于地球上最古老的两类复杂动物——刺胞动物（如水母、珊瑚）和栉水母动物。这些诞生于7.4亿至5.2亿年前的生物，虽然与单细胞祖先共享大量基因，却通过染色质三维结构的重组，发展出多种细胞类型。科学家采用Micro-C染色质构象捕获技术，首次绘制出这些远古生物后代的基因组三维图谱。

研究显示，当DNA片段在空间上形成环状结构时，原本相隔遥远的基因调控元件得以相互接触。这种"染色质环"就像分子级开关，通过不同组合方式激活特定基因，使细胞获得肌肉、神经等特定功能。值得注意的是，现存单细胞生物体内并未发现此类结构。

尽管栉水母等生物基因组较小，却存在数千个此类调控环。科学家推测，这种基因调控的"模块化"创新，使得有限数量的基因通过不同排列组合，创造出惊人的细胞多样性，为寒武纪生命大爆发奠定了分子基础。

该研究为理解生命复杂性演化提供了新视角，但科学家强调，染色质环并非唯一因素，基因组的扩展、新基因的出现等共同推动了这场历时数亿年的进化革命。

中文翻译：

DNA环状结构为远古生命开启复杂演化之路
米里亚姆·瓦雷斯 为量子杂志撰稿
对进化生物学家而言，栉水母与刺胞动物这两类海洋生物最显著的特征，并非它们拗口的名称或惊艳的外形，而是它们作为已知最古老的复杂动物类群所承载的演化密码。刺胞动物家族（包括水母、珊瑚和海葵）用绚丽的触手与褶皱装点着全球海域；栉水母（又称梳状水母）则大多通体透明如凝胶，犹如飘荡在海洋中的幽灵体。

这两类无脊椎动物被认为诞生于7.4亿至5.2亿年前，是最早演化出多种组织类型的多细胞动物。它们的出现提升了动物界的复杂度：相较于之前的单细胞生物，它们在体型结构与组织层次上与人类更为接近。因此刺胞动物与栉水母的演化登场，堪称从原始黏液到人类征程中最关键的跃迁之一。

奥秘何在？
奇特的是，在这些海洋生物体内发现的众多基因，其实早已存在于更古老的单细胞物种中。真正在5.4亿年前寒武纪（或更早）推动复杂动物演化的，并非本质迥异的新基因，而是其他机制。《自然》最新研究揭示了这一谜底。

研究指出，关键在于基因的结构与调控方式——即基因如何表达为功能蛋白，以及其调控机制。领导该研究的巴塞罗那基因组调控中心学者阿尔瑙·塞贝-佩德罗斯表示：“动物起源阶段并未出现大量基因创新，真正重要的是在时空维度上以模块化方式调控基因组合的能力。”

研究团队发现，最早期的复杂动物通过一种奇妙的策略实现了基因调控新模式：将DNA环状结构从染色体缠结中抽出，通过拓扑扭曲使染色体远端区域相互接触。动物复杂性的起源，或许就藏在这些环状结构中。

专业化的驱动力
后生动物（如人类等复杂动物）的起源常被归因于单细胞到多细胞的转变，但细胞协作可能并非难点——黏菌在胁迫下会聚集成团，细菌也能形成生物膜群落。真正的突破在于细胞分化与特化。要构建多种组织，细胞必须分化为肌肉、皮肤、神经等不同类型。尽管刺胞动物与人类差异巨大，但它们已拥有分化细胞类型（单细胞RNA测序显示其细胞种类比预想更丰富）。

同一生物体内所有细胞共享相同基因组，但不同组织通过激活特定基因组合实现功能分化。塞贝-佩德罗斯的同事伊安娜·金解释：“实现稳定细胞分化的核心挑战，在于差异化调控现有基因组合。”未参与研究的索尔克研究所细胞生物学家泰莎·波佩指出：“细胞特化无需巨变，关键在于精准的时空基因表达。”

基因调控的精密装置
德国马普研究所专家玛丽克·奥德拉尔补充：“复杂生物通常拥有更多基因组调控序列。”这些非编码DNA片段通过远程调控基因表达。在多组织生物中，基因调控更为精密：以编码微管蛋白的基因为例，它需在纤毛形成、有丝分裂纺锤体组装及神经元递质运输中发挥作用。金解释道：“这要求该基因在不同细胞中接受特定转录因子组合调控。”

解决方案在于调动染色体远端区域。增强子——这种能远程调控基因的DNA序列，通过形成染色质环状结构拉近与目标基因的距离。染色质首先划分为拓扑关联结构域，其内的环状结构则负责精细调控。这些环状结构由黏连蛋白构筑，CTCF蛋白充当制动器，形成复杂的调控网络。

环状结构的革命
研究团队通过Micro-C技术发现，刺胞动物、栉水母及平板动物（仅具少数细胞类型的简单生物）已具备将启动子与增强子连接的染色质环结构。栉水母虽基因组较小却蕴含数千个此类环状结构，而单细胞生物则完全缺失这种机制。波佩评价：“染色质环促进细胞特化的观点非常合理，哺乳动物研究也证实增强子-启动子环化对细胞身份基因表达至关重要。”

未解的调控密码
目前尚不清楚早期动物如何精确控制环状结构形成——它们缺乏CTCF蛋白，可能使用同家族蛋白替代。增强子在远古生物中的具体作用也存在争议：可能是转录因子结合平台，也可能像脊椎动物那样编码调控RNA。奥德拉尔认为该假说值得探索，但需更多物种证据支持。

以色列魏茨曼研究所专家阿莫斯·塔奈强调：“远程调控促进复杂多细胞性的理念合乎逻辑，但需要更多物种数据支撑。”巴塞罗那进化生物学家伊尼亚基·鲁伊斯-特里略则提醒，现存物种历经数百万年演化，未必能完全代表远古形态。

尽管染色质环化机制至关重要，但非唯一因素。塞贝-佩德罗斯指出，基因组规模扩张等因素同样关键，各要素间的因果链条仍待厘清。塔奈提出下一步应解析调控组合的逻辑规则——当转录因子放弃细菌中的特异性转向组合式调控时，环状结构才真正发挥作用。

若染色质环化确是引爆动物复杂性的关键，则意味着这种潜质早已蛰伏在单细胞祖先的基因组中。鲁伊斯-特里略感叹：“这引发出迷人命题——进化既无方向亦无预见性，为何如此？”更令人遐想的是：现存基因会否因新的调控革新，再次引爆生命形态的飞跃？正如塔奈所言：“进化永远充满惊喜。”

英文来源：

Loops of DNA Equipped Ancient Life To Become Complex
Myriam Wares for Quanta Magazine
For evolutionary biologists, what most distinguishes the marine creatures called cnidarians and ctenophores is not the peculiar spelling of their names, nor the fact that they tend to be beautiful, but that they are among the oldest known groups of complex animals. Cnidarians (the “c” is silent) include jellyfish, corals and sea anemones, and their colorful tendrils and fronds adorn oceans all over the globe. Ctenophores (another silent “c”), otherwise known as comb jellies, are mostly translucent and gelatinous, and they glide through the marine world like ectoplasm.
Thought to have arisen between about 740 million and 520 million years ago, both phyla of marine invertebrates were among the first multicellular animals to evolve several different tissue types. Their appearance ramped up the complexity of the animal world: They are more similar to us in terms of size and organization than they are to the single-celled organisms that came before them. The evolutionary debut of cnidarians and ctenophores thus represented one of the most significant steps in the journey from primordial slime to humans.
What made it possible?
The peculiar thing is that many of the genes identified in these oceanic creatures are also found in the unicellular species that preceded them. It wasn’t fundamentally different genes that kick-started the evolution of complex animals during (or before) the Cambrian period that began 540 million years ago, but something else. In a new study published in Nature, researchers think they have figured out what that was.
The findings build on the idea that it’s not a question of what genes are present, but of how they are structured and used — that is, which genes are expressed, or converted into functional proteins, and how they are regulated. “At the origin of animals, there wasn’t so much gene innovation,” said Arnau Sebé-Pedrós of the Center for Genomic Regulation (CRG) in Barcelona, who led the study. Instead, “an important feature was the capacity to modularly regulate these genes in different combinations in space and time.”
Sebé-Pedrós and his colleagues believe that what made these new patterns of gene regulation and expression possible in the earliest complex animals was a rather bizarre gambit that all multicellular creatures now employ. It involves pulling loops of DNA out of the tangled mass of the chromosomes, and letting the loops undergo topologically complicated contortions to put one part of the chromosome in contact with other parts far away. The origin of animal complexity might literally have been loopy.
Courtesy of Iana Kim and Arnau Sebé-Pedrós
Drive to Specialize
It’s often implied that the big deal in the origin of complex animals like us, known as metazoans, was the switch from unicellular to multicellular life. But getting cells to work together might not actually be that hard. Some single-celled slime molds gather into collective blobs in times of stress, and even many bacteria collaborate in swarms, for example when forming the resilient colonies called biofilms. It’s thought that a transition from single-celled to multicellular might have happened many times over the course of evolution.
The really big deal was that cells became able to differentiate, to specialize. To make the various tissues of metazoans, some cells must become muscle, some skin, some nerves and so on. Cnidarians might seem a long way from bilaterally symmetrical vertebrates like us, yet they still have distinct cell types, although not as many as we do. (Recent studies using the technique of single-cell RNA sequencing have revealed that jellyfish and corals have more distinct cell types than we thought.)
With a few exceptions, all cells in a given organism have the same genome: the same set of DNA in every cell. But those in different tissues use different sets of genes to create their different functions and properties such as shape and elasticity. “To evolve true multicellularity with stable, differentiated cell types, the challenge was to differentially activate or silence the existing set of genes in different cells,” said Sebé-Pedrós’ CRG colleague Iana Kim.
“You don’t actually need that much to change to give a cell a specialty,” said the cell biologist Tessa Popay of the Salk Institute in La Jolla, California, who was not involved in the new work. What matters is “expressing the right genes in the right place at the right time.”
“More complex organisms are thought to have more regulatory sequences in their genome,” said Marieke Oudelaar, an expert in gene regulation at the Max Planck Institute for Multidisciplinary Sciences in Göttingen, Germany, who was also not involved with the study. Regulatory sequences are segments of DNA that don’t code for genes but do control gene expression. In addition to having more of these regulatory sequences, complex organisms also tend to have much bigger genomes, and it’s hard to figure out how these regulatory regions are organized.
Gene regulation is vital in all organisms; even bacteria don’t want all their genes to be active all the time. Usually, in single-celled organisms, a set of proteins called transcription factors (TFs) bind to DNA just “upstream” of a gene, at a site called a promoter, and will activate or suppress transcription of that gene into its respective mRNA, which is the first step in translating the code in the gene into a protein.
Marine Biological Laboratory and BioQuest Studios
But in multicellular, multi-tissue organisms, gene regulation is a more complex process. In any given cell type, certain genes must work together as a module, and a given gene might be involved in several modules in different cell types. Take, for example, the gene that encodes the protein called tubulin. This protein is needed for the formation of cilia — hairlike protrusions that cells can use to move — as well as in the assembly of the mitotic spindle that organizes chromosomes during cell division, and for the transport of neurotransmitters in neurons.
“To be expressed in all these cell types, the tubulin gene would either require a unique TF for each cell or a specific combination of TFs,” Kim said. The first option would result in loads of specialized TFs for each gene in each cell type. Instead, metazoan TFs are less specialized in themselves but can act in pairs or groups — that is, combinatorially, as a module. This way, many different outcomes in different cell types can come from just a few components, much as our eyes can see the whole gamut of colors by using combinations of just three types of wavelength-sensitive cone cells.
However, there’s another problem: how to get all those TFs close to the genes they regulate. “These TFs need to bind in proximity to the gene to regulate it,” Kim said. But the TF binding site — the promoter — only has limited space. “So a gene can only participate in a limited number of modules if regulated only by a proximal region,” Kim said.
The solution is to include more distant parts of the chromosome in the regulatory machinery. DNA sequences that collaborate with promoters to regulate genes from afar are called enhancers and have been known about for several decades. At first they posed a puzzle: Why place a regulatory unit so far away from the gene it regulates (in some cases, hundreds of thousands of DNA base pairs away)? “They provide additional landing spots for TFs, enabling more complex TF code,” Kim said. “This flexibility greatly expands the regulatory potential of the genome. Enhancers make it possible to reuse the same gene in many contexts, contributing to cell-type diversity and functional complexity without expanding the gene count.”
Enhancers make more complex gene regulation possible, but they seem to pose another problem: How can a site far away from a gene have any effect on it? The answer is that cells have ways to close the distance and bring the enhancer in contact with the promoter and gene sequence that it augments. It’s easy to imagine a DNA sequence splayed out in linear fashion, but the double helix is wound around disk-shaped protein units called histones to form a three-dimensional mass called chromatin. There are ways to put distal parts of the chromosome in proximity — if the enhancer can be pulled out of the mass of chromatin and brought close to the promoter and gene on a loop.
Bruno C. Vellutini/Creative Commons
The overall structure of a chromosome can be divided first into large territories, then into more specialized compartments, and then into topologically associating domains, known as TADs. These TADs are often thought of as functional or regulatory “neighborhoods” that put related DNA sequences together. Loops are smaller structures within them that do the finer-scale work of bringing separated parts of the sequence together.
But loops don’t just form via some random fluctuation in chromatin shape; their creation is orchestrated and requires energy. In advanced metazoans like us, a loop of chromatin is constricted at its base by a hoop-shaped protein called cohesin, which acts a bit like the knot of a lasso. The chromatin strand can pass through the hoop until it hits a protein called CTCF that’s bound to DNA and acts as a stopper. In short, distal regulation via chromatin loops is a complicated and costly business, and we can only suppose that the benefits it offered for new regulatory options were worth the effort. It can, for example, greatly enhance the potential for combinatorial complexity. By bringing enhancers to different parts of the chromosome, the loops can not only allow a single enhancer to help regulate more than one gene but also allow a gene to be regulated by more than one enhancer.
In the Loop
Sebé-Pedrós, Kim and their colleagues have now found that chromatin looping seems to have been a significant step in metazoan evolution, one that distinguishes the cnidarians and ctenophores — as well as sponges and placozoans, which were also in the study — from their closest unicellular relatives still living today. The latter are simple eukaryotes with similarly challenging names: ichthyosporeans (which can be parasitic to fish and other marine animals), filastereans (amoebalike organisms with a complex life cycle that includes multicellular aggregation) and choanoflagellates (which can swim and are generally regarded as the closest living relatives of animals).
The team used a technique introduced 10 years ago called Micro-C to reveal which parts of the chromatin are brought physically close to one another. The method involves chemically linking close chromatin regions, and then chopping up the chromatin and observing which sequences in the fragments are bound together. The result is a genome-wide map of chromatin proximity, which encodes the three-dimensional organization of the genome. Techniques like this have been around for some time, but Micro-C uses an enzyme that can cut up DNA more finely than before. “Micro-C has been a game changer for us, because we deal with species with small genomes,” Sebé-Pedrós said, so it’s crucial to be able to divide it up into many tiny fragments.
The researchers found that cnidarians, ctenophores and placozoans (simple, flat animals with just a few cell types) possess a more complex genome architecture than the unicellular animals do, including chromatin loops that bring promoters and enhancers together. Even small genomes, such as those of ctenophores, can hold thousands of such loops, while single-celled organisms show no looping. They also observed these loops coalescing into structures like TADs. These mechanisms for finely tuned and modular gene expression seem to be necessary for more complex body plans and cell specialization, and are a key aspect of how our genomes work.
So, it seems these regulatory innovations may have allowed many kinds of multicellular creatures to arise from a set of genes that don’t appear to have differed that much from those of their evolutionary forebears.
Dillon Parkford and the Salk Institute Postdoctoral Office
“The view that chromatin looping and distal regulatory elements helped enable cell specialization in multicellular organisms is very reasonable,” Popay said. “It is supported by other work in mammalian systems which suggests chromatin looping, particularly between enhancers and promoters, is important to the expression of certain cell-identity genes.”
Rules of Regulation
It’s not yet known quite how cnidarians and ctenophores create chromatin loops to add this extra layer of regulatory complexity to cell-type-specific gene regulation. They probably use cohesin hoops, as our cells do, but they don’t have the CTCF proteins to control where loops start and stop. Sebé-Pedrós thinks that other proteins in the same family might do the same job.
Nor do they know exactly what role the enhancers played in early metazoans. Some researchers think that enhancers might encode RNA molecules that get transcribed and interact with other molecules on the regulatory “committee” that determines gene activation — just as they do in vertebrates like us. But Sebé-Pedrós and colleagues suspect that enhancers in cnidarians and ctenophores are basically just places for additional TFs, and that more well-defined insulation of chromatin domains to modularize gene activity came later, possibly with the evolution of bilateral animals.
“I think this is a very interesting hypothesis,” Oudelaar said. But she cautioned that “while there is certainly nothing that speaks against it at the moment, there is also no concrete evidence for it yet beyond correlations [between looping and organismal complexity].”
Amos Tanay, an expert in genomic regulation at the Weizmann Institute of Science in Rehovot, Israel, agreed. “The idea that long-range regulation facilitates complex multicellularity makes much sense, but I will need to see more results from more species to build confidence in the hypothesis,” he said.
A big challenge is that we don’t know how much early cnidarians and ctenophores look like the species living today, according to Iñaki Ruiz-Trillo, an evolutionary biologist at Pompeu Fabra University in Barcelona. “These lineages have evolved for millions of years, so you cannot take them as a proxy,” he said.
In any event, no one thinks that chromatin looping was the only thing that enabled the rise of complex animals. There was, for example, some genetic novelty too, Sebé-Pedrós said.
And the genomes of these organisms expanded considerably relative to unicellular organisms, even if the number of protein-coding genes did not. The evolutionary changes, he said, were probably due to a combination of factors, and “it’s very difficult to know which aspect triggered the other.”
A first step, Tanay said, is to figure out the logical rules or grammar that govern the regulatory combinations. Looping only really works when TFs abandon the specificity of effect that they show in bacteria and embrace the “fuzziness” of interaction that allows them to work combinatorially. It is not known whether this happened before looping arose. “This is a really exciting question, but we do not have an answer to it,” Sebé-Pedrós said. He says that he and his colleagues are hoping to deduce the molecular rules of regulation in these early metazoans and their unicellular precursors. “It will be exciting to compare these regulatory logics across animal evolution,” he said.
And if chromatin looping was indeed a key innovation that unleashed animal complexity, there’s a puzzling implication: That complexity would seem to have been latent, in a sense, in the genomes of their unicellular ancestors — before evolution had even thought of metazoans, so to speak. It’s not at all obvious why that should have been so; evolution has no universal direction, no foresight. “To me this is a fascinating question,” Ruiz-Trillo said.
To push it even further: Could another burst of regulatory novelty create, from genes that exist today, yet another shift in what living organisms can be? After all, as Tanay said, “Evolution is always full of surprises.”