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Mitotic chromatin marking governs asymmetric segregation of DNA damage. 有丝分裂染色质标记控制DNA损伤的不对称分离。
Pub Date : 2024-09-28 DOI: 10.1101/2023.09.04.556166
Juliette Ferrand, Juliette Dabin, Odile Chevallier, Matteo Kane-Charvin, Ariana Kupai, Joel Hrit, Scott B Rothbart, Sophie E Polo

The faithful segregation of intact genetic material and the perpetuation of chromatin states through mitotic cell divisions are pivotal for maintaining cell function and identity across cell generations. However, most exogenous mutagens generate long-lasting DNA lesions that are segregated during mitosis. How this segregation is controlled is unknown. Here, we uncover a mitotic chromatin-marking pathway that governs the segregation of UV-induced damage in human cells. Our mechanistic analyses reveal two layers of control: histone ADP-ribosylation, and the incorporation of newly synthesized histones at UV damage sites, that both prevent local mitotic phosphorylations on histone H3 serine residues. Functionally, this chromatin-marking pathway drives the asymmetric segregation of UV damage in the cell progeny with consequences on daughter cell fate. We propose that this mechanism may help preserve the integrity of stem cell compartments during asymmetric cell divisions.

完整遗传物质的忠实分离和染色质状态通过有丝分裂细胞分裂的持久化对于在细胞世代中维持细胞功能和身份至关重要。然而,大多数外源性诱变剂会产生持久的DNA损伤,这些损伤在有丝分裂过程中被分离。这种隔离是如何控制的还不得而知。在这里,我们揭示了一种有丝分裂染色质标记途径,它控制着人类细胞中紫外线诱导损伤的分离。我们的机制分析揭示了两层控制:组蛋白ADP核糖基化和新合成的组蛋白在紫外线损伤位点的结合,这两层都可以防止组蛋白H3丝氨酸的局部有丝分裂磷酸化。从功能上讲,这种染色质标记途径驱动细胞子代中紫外线损伤的不对称分离,并对子细胞命运产生潜在影响。我们提出,这种机制可能有助于在不对称细胞分裂过程中保持干细胞区室的完整性。
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引用次数: 0
Structural prediction of chimeric immunogens to elicit targeted antibodies against betacoronaviruses. 嵌合免疫原引发针对β冠状病毒的靶向抗体的结构预测。
Pub Date : 2024-09-28 DOI: 10.1101/2023.01.31.526494
Jamel Simpson, Peter M Kasson

Betacoronaviruses pose an ongoing pandemic threat. Antigenic evolution of the SARS-CoV-2 virus has shown that much of the spontaneous antibody response is narrowly focused rather than broadly neutralizing against even SARS-CoV-2 variants, let alone future threats. One way to overcome this is by focusing the antibody response against better-conserved regions of the viral spike protein. Here, we present a design approach to predict stable chimeras between SARS-CoV-2 and other coronaviruses, creating synthetic spike proteins that display a desired conserved region and vary other regions. We leverage AlphaFold to predict chimeric structures and create a new metric for scoring chimera stability based on AlphaFold outputs. We evaluated 114 candidate spike chimeras using this approach. Top chimeras were further evaluated using molecular dynamics simulation as an intermediate validation technique, showing good stability compared to low-scoring controls. Experimental testing of five predicted-stable and two predicted-unstable chimeras confirmed 5/7 predictions, with one intermediate result. This demonstrates the feasibility of the underlying approach, which can be used to design custom immunogens to focus the immune response against a desired viral glycoprotein epitope.

Betacoronavirus构成了持续的流行病威胁。严重急性呼吸系统综合征冠状病毒2型病毒的抗原进化表明,大部分自发抗体反应都是狭隘的,而不是广泛中和,甚至可以对抗严重急性呼吸系冠状病毒2型变种,更不用说未来的威胁了。克服这一问题的一种方法是将抗体反应集中在病毒刺突蛋白的更好保守区域。在这里,我们提出了一种设计方法来预测严重急性呼吸系统综合征冠状病毒2型和其他冠状病毒之间的稳定嵌合体,创造出显示所需保守区域并改变其他区域的合成刺突蛋白。我们利用AlphaFold来预测嵌合结构,并基于AlphaFol德的输出创建了一个新的嵌合稳定性评分指标。我们使用这种方法评估了114个候选刺突嵌合体。使用分子动力学模拟作为中间验证技术对顶部嵌合体进行了进一步评估,与低评分对照相比显示出良好的稳定性。这证明了潜在方法的可行性,该方法可用于设计定制免疫原,以集中针对所需病毒糖蛋白表位的免疫反应。
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引用次数: 0
Syngap1 Promotes Cognitive Function through Regulation of Cortical Sensorimotor Dynamics. 支持感知的感觉运动整合需要Syngap1在皮层中的表达。
Pub Date : 2024-09-27 DOI: 10.1101/2023.09.27.559787
Thomas Vaissiere, Sheldon D Michaelson, Thomas Creson, Jessie Goins, Daniel Fürth, Diana Balazsfi, Camilo Rojas, Randall Golovin, Konstantinos Meletis, Courtney A Miller, Daniel O'Connor, Lorenzo Fontolan, Gavin Rumbaugh

Perception, a cognitive construct, emerges through sensorimotor integration (SMI). The genetic mechanisms that shape SMI required for perception are unknown. Here, we demonstrate in mice that expression of the autism/intellectual disability gene, Syngap1, in cortical excitatory neurons is required for formation of somatomotor networks that promote SMI-mediated perception. Cortical Syngap1 expression was necessary and sufficient for setting tactile sensitivity, sustaining tactile object exploration, and promoting tactile learning. Mice with deficient Syngap1 expression exhibited impaired neural dynamics induced by exploratory touches within a cortical-thalamic network known to promote attention and perception. Disrupted neuronal dynamics were associated with circuit-specific long-range synaptic connectivity abnormalities. Our data support a model where autonomous Syngap1 expression in cortical excitatory neurons promotes cognitive abilities through assembly of circuits that integrate temporally-overlapping sensory and motor signals, a process that promotes perception and attention. These data provide systems-level insights into the robust association between Syngap1 expression and cognitive ability.

感知是一种认知结构,通过感觉运动整合(SMI)产生。在促进认知的电路中形成SMI的分子和细胞机制尚不清楚。在这里,我们证明了自闭症/智力残疾基因Syngap1在小鼠皮层兴奋性神经元中的表达促进了引发感知行为所需的触摸敏感性。皮层突触间隙1的表达通过组装支持触觉敏感性的电路,在感觉运动回路中实现触摸诱导的反馈信号。这些回路还编码了注意力的相关性,这些相关性促进了有目的和持续的物体探索背后的自我生成的胡须运动。当Syngap1缺陷动物探索有胡须的物体时,相对较弱的触摸信号与相对较强的运动信号相结合。这产生了与触觉敏感性受损、触觉探索减少和触觉学习薄弱一致的信噪比缺陷。因此,皮层中Syngap1的表达通过组装整合触摸和胡须运动信号的电路来促进触觉感知。Syngap1表达不足可能通过自上而下的异常SMI导致认知障碍。
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引用次数: 0
"Distinct inhibitory neurons differently shape neuronal codes for sound intensity in the auditory cortex". 由不同的抑制性神经元亚型控制的听觉皮层中声音的局部表示与分布表示。
Pub Date : 2024-09-27 DOI: 10.1101/2023.02.01.526470
Melanie Tobin, Janaki Sheth, Katherine C Wood, Erin K Michel, Maria N Geffen

Cortical circuits contain multiple types of inhibitory neurons which shape how information is processed within neuronal networks. Here, we asked whether somatostatin-expressing (SST) and vasoactive intestinal peptide-expressing (VIP) inhibitory neurons have distinct effects on population neuronal responses to noise bursts of varying intensities. We optogenetically stimulated SST or VIP neurons while simultaneously measuring the calcium responses of populations of hundreds of neurons in the auditory cortex of male and female awake, head-fixed mice to sounds. Upon SST neuronal activation, noise bursts representations became more discrete for different intensity levels, relying on cell identity rather than strength. By contrast, upon VIP neuronal activation, noise bursts of different intensity level activated overlapping neuronal populations, albeit at different response strengths. At the single-cell level, SST and VIP neuronal activation differentially modulated the response-level curves of monotonic and nonmonotonic neurons. SST neuronal activation effects were consistent with a shift of the neuronal population responses toward a more localist code with different cells responding to sounds of different intensity. By contrast, VIP neuronal activation shifted responses towards a more distributed code, in which sounds of different intensity level are encoded in the relative response of similar populations of cells. These results delineate how distinct inhibitory neurons in the auditory cortex dynamically control cortical population codes. Different inhibitory neuronal populations may be recruited under different behavioral demands, depending on whether categorical or invariant representations are advantageous for the task.

皮层神经元群体可以使用多种代码来表示信息,每种代码都有不同的优势和权衡。听觉皮层通过稀疏编码来表示声音,稀疏编码位于不同细胞对不同声音做出反应的局部表示和分布式表示之间的连续体上,在分布式表示中,每个声音都被编码在群体中每个细胞的相对响应中。能够沿着这个轴动态地移动神经元代码可能有助于完成各种需要分类或不变表示的任务。皮层回路包含多种类型的抑制性神经元,这些神经元决定了神经元网络中信息的处理方式。在这里,我们询问了表达生长抑素(SST)和表达血管活性肠肽(VIP)的抑制性神经元是否对群体神经元编码有不同的影响,从而在分布和局部表征之间差异地改变声音的编码。我们刺激光遗传学SST或VIP神经元,同时测量数百个神经元群体对不同声压级声音的反应。SST激活使神经元群体反应向更本地化的代码转移,而VIP激活使其向更分布式的代码转移。SST激活后,声音表征变得更加离散,依赖于细胞身份而非强度。相反,在VIP激活时,不同的声音以不同的速率激活重叠的群体。这些变化是通过调节单调和非单调神经元的反应水平曲线在单细胞水平上实现的。这些结果表明,听觉皮层中不同的抑制性神经元在动态控制皮层群体代码方面具有新的功能。
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引用次数: 0
Forecasting dominance of SARS-CoV-2 lineages by anomaly detection using deep AutoEncoders. 利用深度自动编码器异常检测预测SARS-CoV-2谱系的优势性。
Pub Date : 2024-09-26 DOI: 10.1101/2023.10.24.563721
Simone Rancati, Giovanna Nicora, Mattia Prosperi, Riccardo Bellazzi, Marco Salemi, Simone Marini

The coronavirus disease of 2019 (COVID-19) pandemic is characterized by sequential emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, lineages, and sublineages, outcompeting previously circulating ones because of, among other factors, increased transmissibility and immune escape. We propose DeepAutoCoV, an unsupervised deep learning anomaly detection system to predict future dominant lineages (FDLs). We define FDLs as viral (sub)lineages that will constitute more than 10% of all the viral sequences added to the GISAID database on a given week. DeepAutoCoV is trained and validated by assembling global and country-specific data sets from over 16 million Spike protein sequences sampled over a period of about 4 years. DeepAutoCoV successfully flags FDLs at very low frequencies (0.01% - 3%), with median lead times of 4-17 weeks, and predicts FDLs ~5 and ~25 times better than a baseline approach For example, the B.1.617.2 vaccine reference strain was flagged as FDL when its frequency was only 0.01%, more than a year before it was considered for an updated COVID-19 vaccine. Furthermore, DeepAutoCoV outputs interpretable results by pinpointing specific mutations potentially linked to increased fitness, and may provide significant insights for the optimization of public health pre-emptive intervention strategies.

COVID-19大流行表明,需要一个快速、有效的基于基因组的监测系统来预测新出现的SARS-CoV-2变体和谱系。利用公共卫生监测或综合序列数据库的传统分子流行病学方法能够表征感染波和遗传进化的进化史,但在预测病毒遗传改变的未来前景方面存在不足。为了弥补这一差距,我们引入了一种新的基于深度学习、自动编码器的SARS-CoV-2异常检测方法(DeepAutoCov)。对全球公共SARS-CoV-2 GISAID数据库进行培训并更新。DeepAutoCov识别未来优势谱系(fdl),定义为每周使用Spike (S)蛋白,每周添加至少25%的SARS-CoV-2基因组的谱系。我们的算法基于通过无监督方法进行异常检测,这是必要的,因为fdl只能是后验的(即,在它们成为主导之后)。我们开发了两种并发方法(线性无监督和后验监督)来评估DeepAutoCoV的性能。DeepAutoCoV使用刺突(S)蛋白识别FDL,在全球数据上的中位提前期为31周,比其他方法获得的阳性预测值高出约7倍,高出23%。此外,它还可以提前17个月预测与疫苗相关的fdl。最后,DeepAutoCoV不仅具有预测性,而且具有可解释性,因为它可以确定fdl中的特定突变,从而产生关于谱系毒性或传播性潜在增加的假设。通过将基因组监测与人工智能相结合,我们的工作标志着一个变革性的步骤,可能为优化公共卫生预防和干预策略提供有价值的见解。
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引用次数: 0
Clustering-independent estimation of cell abundances in bulk tissues using single-cell RNA-seq data. 使用单细胞RNA-seq数据对大块组织中细胞丰度进行聚类独立估计。
Pub Date : 2024-09-25 DOI: 10.1101/2023.02.06.527318
Rachael G Aubin, Javier Montelongo, Robert Hu, Elijah Gunther, Patrick Nicodemus, Pablo G Camara

Single-cell RNA-sequencing has transformed the study of biological tissues by enabling transcriptomic characterizations of their constituent cell states. Computational methods for gene expression deconvolution use this information to infer the cell composition of related tissues profiled at the bulk level. However, current deconvolution methods are restricted to discrete cell types and have limited power to make inferences about continuous cellular processes like cell differentiation or immune cell activation. We present ConDecon, a clustering-independent method for inferring the likelihood for each cell in a single-cell dataset to be present in a bulk tissue. ConDecon represents an improvement in phenotypic resolution and functionality with respect to regression-based methods. Using ConDecon, we discover the implication of neurodegenerative microglia inflammatory pathways in the mesenchymal transformation of pediatric ependymoma and characterize their spatial trajectories of activation. The generality of this approach enables the deconvolution of other data modalities such as bulk ATAC-seq data.

单细胞RNA测序通过对生物组织组成细胞状态进行转录组学表征,改变了对生物组织的研究。基因表达去卷积的计算方法使用这些信息来推断在体积水平上描述的相关组织的细胞组成。然而,目前的去卷积方法仅限于离散的细胞类型,并且对连续的细胞过程(如细胞分化或免疫细胞激活)进行推断的能力有限。我们提出了ConDecon,这是一种独立于聚类的方法,用于推断单细胞数据集中每个细胞存在于大块组织中的可能性。ConDecon代表了相对于当前反褶积方法在功能性和准确性方面的改进。使用ConDecon,我们发现了神经退行性小胶质细胞炎症途径在室管膜瘤间充质转化中的意义,概括了斑马鱼胚胎发生过程中细胞分化的空间模式,并从大量ATAC-seq数据中进行了时间推断。总体而言,ConDecon显著增强了我们对大块组织样本中动态细胞过程的理解。
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引用次数: 0
Highly sensitive in vivo detection of dynamic changes in enkephalins following acute stress. 高灵敏度体内检测急性应激后脑啡肽的动态变化。
Pub Date : 2024-09-25 DOI: 10.1101/2023.02.15.528745
Marwa O Mikati, Petra Erdmann-Gilmore, Rose Connors, Sineadh M Conway, Jim Malone, Justin Woods, Robert W Sprung, R Reid Townsend, Ream Al-Hasani

Enkephalins are opioid peptides that modulate analgesia, reward, and stress. In vivo detection of enkephalins remains difficult due to transient and low endogenous concentrations and inherent sequence similarity. To begin to address this we previously developed a system combining in vivo optogenetics with microdialysis and a highly sensitive mass spectrometry-based assay to measure opioid peptide release in freely moving rodents (Al-Hasani, 2018, eLife). Here we show improved detection resolution and stabilization of enkephalin detection, which allowed us to investigate enkephalin release during acute stress. We present an analytical method for real-time, simultaneous detection of Met- and Leu-Enkephalin (Met-Enk & Leu-Enk) in the mouse Nucleus Accumbens shell (NAcSh) after acute stress. We confirm that acute stress activates enkephalinergic neurons in the NAcSh using fiber photometry and that this leads to the release of Met- and Leu-Enk. We also demonstrate the dynamics of Met- and Leu-Enk release as well as how they correlate to one another in the ventral NAc shell, which was previously difficult due to the use of approaches that relied on mRNA transcript levels rather than post-translational products. This approach increases spatiotemporal resolution, optimizes the detection of Met-Enkephalin through methionine oxidation, and provides novel insight into the relationship between Met- and Leu-Enkephalin following stress.

脑啡肽是一种阿片肽,可调节镇痛、奖赏和压力。由于脑啡肽的内源性浓度短暂且较低,再加上其固有的序列相似性,因此脑啡肽的体内检测仍然十分困难。为了着手解决这个问题,我们之前开发了一套系统,将体内光遗传学与微透析和基于质谱的高灵敏度检测相结合,测量自由活动的啮齿动物体内阿片肽的释放(Al-Hasani,2018,eLife)。在这里,我们展示了检测分辨率的提高和脑啡肽检测的稳定,这使我们能够研究急性应激期间脑啡肽的释放。我们提出了一种分析方法,用于在急性应激后实时、同时检测小鼠延脑核壳(NAcSh)中的Met-和Leu-脑啡肽(Met-Enk & Leu-Enk)。我们利用纤维光度法证实,急性应激激活了 NAcSh 中的脑啡肽能神经元,并导致释放 Met- 和 Leu-Enk。我们还展示了Met-和Leu-Enk释放的动态,以及它们在NAc腹侧外壳中如何相互关联,这在以前是很难做到的,因为我们使用的方法依赖于mRNA转录水平而不是翻译后产物。这种方法提高了时空分辨率,优化了通过蛋氨酸氧化检测元脑啡肽的过程,并为了解应激后元脑啡肽和亮脑啡肽之间的关系提供了新的视角。
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引用次数: 0
Ultrafast Power Doppler Ultrasound Enables Longitudinal Tracking of Vascular Changes that Correlate with Immune Response After Radiotherapy. 超声成像可纵向追踪放疗后与免疫反应相关的血管变化
Pub Date : 2024-09-25 DOI: 10.1101/2023.08.04.552076
Shannon E Martello, Jixin Xia, Jiro Kusunose, Benjamin C Hacker, McKenzie A Mayeaux, Erica J Lin, Adrienne Hawkes, Aparna Singh, Charles F Caskey, Marjan Rafat

Background: While immunotherapy shows great promise in patients with triple negative breast cancer, many will not respond to treatment. Radiotherapy has the potential to prime the tumor-immune microenvironment for immunotherapy. However, predicting response is difficult due to tumor heterogeneity across patients, which necessitates personalized medicine strategies that incorporate tumor tracking into the therapeutic approach. Here, we investigated the use of ultrasound (US) imaging of the tumor vasculature to monitor the tumor response to treatment.

Methods: We utilized ultrafast power doppler US to track the vascular response to radiotherapy over time. We used 4T1 (metastatic) and 67NR (non-metastatic) breast cancer models to determine if US measurements corroborate conventional immunostaining analysis of the tumor vasculature. To evaluate the effects of radiation, tumor volume and vascular index were calculated using US, and the correlation between vascular changes and immune cell infiltration was determined.

Results: US tumor measurements and the quantified vascular response to radiation were confirmed with caliper measurements and immunostaining, respectively, demonstrating a proof-of-principle method for non-invasive vascular monitoring. Additionally, we found significant infiltration of CD8 + T cells into irradiated tumors 10 days after radiation, which followed a sustained decline in vascular index and an increase in splenic CD8 + T cells that was first observed 1 day post-radiation.

Conclusions: Our findings reveal that ultrafast power doppler US can evaluate changes in tumor vasculature that are indicative of shifts in the tumor-immune microenvironment. This work may lead to improved patient outcomes through observing and predicting response to therapy.

背景:虽然免疫疗法在三阴性乳腺癌患者中大有可为,但许多患者对治疗无效。放疗有可能为免疫疗法提供肿瘤免疫微环境。然而,由于不同患者的肿瘤具有异质性,因此很难预测反应,这就需要将肿瘤追踪纳入治疗方法的个性化医疗策略。在此,我们研究了利用肿瘤血管的超声(US)成像来监测肿瘤对治疗的反应:方法:我们利用超快功率多普勒超声来纵向追踪血管对放疗的反应。我们使用 4T1(转移性)和 67NR(非转移性)乳腺癌模型来确定 US 测量是否与肿瘤血管的传统组织学分析相吻合。为了评估辐射的影响,我们用 US 计算了肿瘤体积和血管指数,并确定了血管变化与免疫细胞浸润之间的相关性:结果:US 测量的肿瘤体积和量化的血管对辐射的反应分别得到了卡尺测量和免疫组化染色的证实,证明这是一种非侵入性血管监测的原理性方法。此外,我们发现 CD8 + T 细胞在辐射 10 天后明显浸润到受辐射的肿瘤中,随后血管指数持续下降,脾脏 CD8 + T 细胞增加,这在辐射 1 天后首次观察到:我们的研究结果表明,超快功率多普勒 US 可以评估肿瘤血管的变化,这些变化表明肿瘤免疫微环境发生了变化。这项工作可通过观察和预测对治疗的反应来改善患者的预后。
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引用次数: 0
Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by ATF4 following optic nerve injury. 视神经损伤后 Atf4 对轴突再生和神经退行性转录程序的协调刺激
Pub Date : 2024-09-25 DOI: 10.1101/2023.03.29.534798
Preethi Somasundaram, Madeline M Farley, Melissa A Rudy, Katya Sigal, Andoni I Asencor, David G Stefanoff, Malay Shah, Puneetha Goli, Jenny Heo, Shufang Wang, Nicholas M Tran, Trent A Watkins

Stress signaling is important for determining the fates of neurons following axonal insults. Previously we showed that the stress-responsive kinase PERK contributes to injury-induced neurodegeneration (Larhammar et al., 2017). Here we show that PERK acts primarily through Activating Transcription Factor-4 (ATF4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve damage. Using conditional knockout mice, we find an extensive PERK/ATF4-dependent transcriptional response that includes canonical ATF4 target genes and modest contributions by C/EBP Homologous Protein (CHOP). Overlap with c-Jun-dependent transcription suggests interplay with a parallel stress pathway that orchestrates regenerative and apoptotic responses. Accordingly, neuronal knockout of ATF4 recapitulates the neuroprotection afforded by PERK deficiency, and PERK or ATF4 knockout impairs optic axon regeneration enabled by disrupting the tumor suppressor PTEN. These findings reveal an integral role for PERK/ATF4 in coordinating neurodegenerative and regenerative responses to CNS axon injury.

此前我们曾发现,轴突损伤引发的神经退行性变部分取决于应激反应激酶Perk(Larhammar等人,2017年)。在这里,我们发现 Perk 主要通过活化转录因子-4(Atf4)发挥作用,在视神经损伤后不仅刺激促凋亡反应,还刺激促再生反应。利用条件性基因敲除小鼠,我们发现了广泛的 Perk/Atf4 依赖性转录反应,其中包括典型的 Atf4 靶基因和 C/ebp 同源蛋白(Chop)的适度贡献。与 c-Jun 依赖性转录的重叠表明,与再生和凋亡反应相关的平行应激途径也在发挥作用。因此,神经元敲除 Atf4 可重现 Perk 缺乏所提供的神经保护,而 Perk 或 Atf4 的敲除会损害肿瘤抑制因子 Pten 所实现的视轴突再生。这些发现与所报道的CRISPR靶向Atf4或Chop的转录和功能后果形成了鲜明对比,并揭示了Perk/Atf4在协调神经退行性病变和中枢神经系统轴突损伤再生反应中不可或缺的作用。
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引用次数: 0
Cohesin organizes 3D DNA contacts surrounding active enhancers in C. elegans. 在秀丽隐杆线虫中,活性增强子的内聚素介导的环挤出形成染色质射流。
Pub Date : 2024-09-25 DOI: 10.1101/2023.09.18.558239
Jun Kim, Haoyu Wang, Sevinç Ercan

In mammals, cohesin and CTCF organize the 3D genome into topologically associated domains (TADs) to regulate communication between cis-regulatory elements. Many organisms, including S. cerevisiae, C. elegans, and A. thaliana contain cohesin but lack CTCF. Here, we used C. elegans to investigate the function of cohesin in 3D genome organization in the absence of CTCF. Using Hi-C data, we observe cohesin-dependent features called "fountains", which are also reported in zebrafish and mice. These are population average reflections of DNA loops originating from distinct genomic regions and are ~20-40 kb in C. elegans. Hi-C analysis upon cohesin and WAPL depletion support the idea that cohesin is preferentially loaded at NIPBL occupied sites and loop extrudes in an effectively two-sided manner. ChIP-seq analyses show that cohesin translocation along the fountain trajectory depends on a fully intact complex and is extended upon WAPL-1 depletion. Hi-C contact patterns at individual fountains suggest that cohesin processivity is unequal on each side, possibly due to collision with cohesin loaded from surrounding sites. The putative cohesin loading sites are closest to active enhancers and fountain strength is associated with transcription. Compared to mammals, average processivity of C. elegans cohesin is ~10-fold shorter and NIPBL binding does not depend on cohesin. We propose that preferential loading and loop extrusion by cohesin is an evolutionarily conserved mechanism that regulates the 3D interactions of enhancers in animal genomes.

在哺乳动物中,粘着蛋白和CTCF将3D基因组组织成拓扑相关结构域(TAD),以调节顺式调控元件之间的通讯。然而,包括酿酒酵母、秀丽隐杆线虫和拟南芥在内的许多生物缺乏CTCF。在这里,我们使用秀丽隐杆线虫作为模型来研究粘附素在没有CTCF的动物的3D基因组组织中的功能。我们使用生长素诱导的降解来从体细胞中急性消耗SMC-3或其负调控因子WAPL-1。使用Hi-C数据,我们确定了一种称为染色质射流(又名喷泉)的粘附素依赖性3D基因组特征,也在斑马鱼和哺乳动物基因组中观察到。射流从NIPBL占据的段中出现,射流的轨迹与凝聚态结合一致。射流起源的凝聚素的扩散取决于完全完整的凝聚素复合体,并在WAPL-1耗尽时扩展。这些结果支持了内聚素优先负载在NIPBL占据的位点的观点,内聚素环以有效的双侧方式从该位点挤出。假定负载位点的位置与活性增强子一致,染色质射流的模式与转录相关。我们提出,在缺乏CTCF的情况下,粘附素在增强子上的优先负载是基因组组织的一种保守机制,它调节3D中基因调控元件的相互作用。
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引用次数: 0
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