Function and Evolution of the Loop Extrusion Machinery in Animals

Kabirova, Evelyn; Nurislamov, Artem; Shadskiy, Artem; Smirnov, A. V.; Popov, Andrey; Salnikov, Pavel; Battulin, Nariman; Fishman, Veniamin

doi:10.3390/ijms24055017

Cited by 14 publications

(11 citation statements)

References 179 publications

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“…For example, research has shown that gene expression can be influenced by variants situated hundreds or even millions of base pairs distant from the promoter. This can be attributed to processes such as loop extrusion [49] and other 3D-genomic mechanisms [50]. There are several strategies to address this constraint in GENA.…”

Section: Discussionmentioning

confidence: 99%

GENA-LM: A Family of Open-Source Foundational DNA Language Models for Long Sequences

Fishman

Kuratov

Petrov³

et al. 2023

Preprint

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The field of genomics has seen substantial advancements through the application of artificial intelligence (AI), with machine learning revealing the potential to interpret genomic sequences without necessitating an exhaustive experimental analysis of all the intricate and interconnected molecular processes involved in DNA functioning. However, precise decoding of genomic sequences demands the comprehension of rich contextual information spread over thousands of nucleotides. Presently, only a few architectures exist that can process such extensive inputs, and they require exceptional computational resources. To address this need, we introduce GENA-LM, a suite of transformer-based foundational DNA language models capable of handling input lengths up to 36 thousands base pairs. We offer pre-trained versions of GENA-LM and demonstrate their capacity for fine-tuning to address complex biological questions with modest computational requirements. We also illustrate diverse applications of GENA-LM for various downstream genomic tasks, showcasing its performance in either matching or exceeding that of prior models, whether task-specific or universal. All models are publicly accessible on GitHub https://github.com/AIRI-Institute/GENA_LM and as pre-trained models with gena-lm- prefix on HuggingFace https://huggingface.co/AIRI-Institute .

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Section: Discussionmentioning

confidence: 99%

GENA-LM: A Family of Open-Source Foundational DNA Language Models for Long Sequences

Fishman

Kuratov

Petrov³

et al. 2023

Preprint

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“…Chromatin architectural proteins play a crucial role in maintaining the three-dimensional structure of the genome (Kabirova et al, 2023). Among them, special attention is drawn to the cohesin and condensin complexes belonging to the SMC (structural maintenance of chromosomes) family of proteins.…”

Section: Introductionmentioning

confidence: 99%

Assessing cell lines with inducible depletion of cohesin and condensins components through analysis of metaphase chromosome morphology

Yunusova,

Smirnov,

Pristyazhnuk

et al. 2024

Vestn. VOGiS

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One of the most productive strategies for finding the functions of proteins is to study the consequences of loss of protein function. For this purpose, cells or organisms with a knockout of the gene encoding the protein of interest are obtained. However, many proteins perform important functions and cells or organisms could suddenly lose fitness when the function of a protein is lost. For such proteins, the most productive strategy is to use in ducible protein degradation systems. A system of auxin-dependent protein degradation is often implemented. To use this system, it is sufficient to introduce a transgene encoding a plant-derived auxin-dependent ubiquitin ligase into mammalian cells and insert a sequence encoding a degron domain into the gene of interest. A crucial aspect of development of cell lines engineered for inducible protein depletion is the selection of cell clones with efficient auxin-dependent degradation of the protein of interest. To select clones induced by depletion of the architectural chromatin proteins RAD21 (a component of the cohesin complex) and SMC2 (a component of the condensin complex), we propose to use the morphology of metaphase chromosomes as a convenient functional test. In this work, we obtained a series of clones of human HAP1 cells carrying the necessary genetic constructs for inducible depletion of RAD21 and SMC2. The degradation efficiency of the protein of interest was assessed by flow cytometry, Western blotting and metaphase chromosome morphology test. Based on our tests, we showed that the clones we established with the SMC2 degron effectively and completely lose protein function when induced by auxin. However, none of the HAP1 clones we created with the RAD21 degron showed complete loss of RAD21 function upon induction of degradation by auxin. In addition, some clones showed evidence of loss of RAD21 function even in the absence of induction. The chromosome morphology test turned out to be a convenient and informative method for clone selection. The results of this test are in good agreement with flow cytometry analysis and Western blotting data.

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“…The spatial architecture of interphase chromosomes has been demonstrated to be nonrandom, with chromatin all along partitioned into topologically associating domains (TADs), shaped by the extruding activity of cohesin 5 . CTCF, a DNA binding protein, halts cohesin extrusion at CTCF binding sites, thereby forming TAD boundaries.…”

Section: Introductionmentioning

confidence: 99%

“…Despite extensive research, there are conflicting findings regarding the functional significance of TAD boundaries. While it is evident that some boundary disruptions can cause disease, not all alterations result in detectable phenotypic abnormalities 5 , 7 . Although computational models capable of predicting chromatin contact alterations for specified chromosomal rearrangements exist 8 , they currently do not offer a level of interpretation suitable for clinical application 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

Structural variants in the Epb41l4a locus: TAD disruption and Nrep gene misregulation as hypothetical drivers of neurodevelopmental outcomes

Salnikov,

Korablev,

Serova

et al. 2024

Sci Rep

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Structural variations are a pervasive feature of human genomes, and there is growing recognition of their role in disease development through their impact on spatial chromatin architecture. This understanding has led us to investigate the clinical significance of CNVs in noncoding regions that influence TAD structures. In this study, we focused on the Epb41l4a locus, which contains a highly conserved TAD boundary present in both human chromosome 5 and mouse chromosome 18, and its association with neurodevelopmental phenotypes. Analysis of human data from the DECIPHER database indicates that CNVs within this locus, including both deletions and duplications, are often observed alongside neurological abnormalities, such as dyslexia and intellectual disability, although there is not enough evidence of a direct correlation or causative relationship. To investigate these possible associations, we generated mouse models with deletion and inversion mutations at this locus and carried out RNA-seq analysis to elucidate gene expression changes. We found that modifications in the Epb41l4a TAD boundary led to dysregulation of the Nrep gene, which plays a crucial role in nervous system development. These findings underscore the potential pathogenicity of these CNVs and highlight the crucial role of spatial genome architecture in gene expression regulation.

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Function and Evolution of the Loop Extrusion Machinery in Animals

Cited by 14 publications

References 179 publications

GENA-LM: A Family of Open-Source Foundational DNA Language Models for Long Sequences

GENA-LM: A Family of Open-Source Foundational DNA Language Models for Long Sequences

Assessing cell lines with inducible depletion of cohesin and condensins components through analysis of metaphase chromosome morphology

Structural variants in the Epb41l4a locus: TAD disruption and Nrep gene misregulation as hypothetical drivers of neurodevelopmental outcomes

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