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1.
Nature ; 623(7985): 183-192, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37853125

RESUMO

The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated1,2, the contribution of chromosome folding to these processes remains unclear3. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer-polymer phase separation rather than liquid-liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.


Assuntos
Compartimento Celular , Cromatina , Dano ao DNA , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular , Cromatina/genética , Cromatina/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Proteína Quinase Ativada por DNA/metabolismo , Fase G1 , Histonas/metabolismo , Neoplasias/genética , Estruturas R-Loop , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
2.
Mol Cell ; 78(3): 376-378, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386540

RESUMO

Using Micro-C, Hsieh et al. (2020) and Krietenstein et al. (2020) investigated 3D chromatin folding in human and mouse cells at unprecedented resolution to uncover ultra-fine-scale chromatin structures that provide direct links between genome architecture, gene expression, and gene regulation.


Assuntos
Cromatina , Genoma , Animais , Regulação da Expressão Gênica , Humanos , Mamíferos , Camundongos
3.
Nature ; 590(7847): 660-665, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33597753

RESUMO

The repair of DNA double-strand breaks (DSBs) is essential for safeguarding genome integrity. When a DSB forms, the PI3K-related ATM kinase rapidly triggers the establishment of megabase-sized, chromatin domains decorated with phosphorylated histone H2AX (γH2AX), which act as seeds for the formation of DNA-damage response foci1. It is unclear how these foci are rapidly assembled to establish a 'repair-prone' environment within the nucleus. Topologically associating domains are a key feature of 3D genome organization that compartmentalize transcription and replication, but little is known about their contribution to DNA repair processes2,3. Here we show that topologically associating domains are functional units of the DNA damage response, and are instrumental for the correct establishment of γH2AX-53BP1 chromatin domains in a manner that involves one-sided cohesin-mediated loop extrusion on both sides of the DSB. We propose a model in which H2AX-containing nucleosomes are rapidly phosphorylated as they actively pass by DSB-anchored cohesin. Our work highlights the importance of chromosome conformation in the maintenance of genome integrity and demonstrates the establishment of a chromatin modification by loop extrusion.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , DNA/química , DNA/metabolismo , Conformação de Ácido Nucleico , Saccharomyces cerevisiae , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proteínas Cromossômicas não Histona/metabolismo , DNA/genética , Genoma/genética , Histonas/metabolismo , Humanos , Nucleossomos/química , Nucleossomos/genética , Nucleossomos/metabolismo , Fosforilação , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Coesinas
4.
Bioessays ; : e2400137, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093600

RESUMO

TAD boundaries are genomic elements that separate biological processes in neighboring domains by blocking DNA loops that are formed through Cohesin-mediated loop extrusion. Most TAD boundaries consist of arrays of binding sites for the CTCF protein, whose interaction with the Cohesin complex blocks loop extrusion. TAD boundaries are not fully impermeable though and allow a limited amount of inter-TAD loop formation. Based on the reanalysis of Nano-C data, a multicontact Chromosome Conformation Capture assay, we propose a model whereby clustered CTCF binding sites promote the successive stalling of Cohesin and subsequent dissociation from the chromatin. A fraction of Cohesin nonetheless achieves boundary read-through. Due to a constant rate of Cohesin dissociation elsewhere in the genome, the maximum length of inter-TAD loops is restricted though. We speculate that the DNA-encoded organization of stalling sites regulates TAD boundary permeability and discuss implications for enhancer-promoter loop formation and other genomic processes.

5.
Nucleic Acids Res ; 2024 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-39180406

RESUMO

During mammalian embryogenesis, both the 5-cytosine DNA methylation (5meC) landscape and three dimensional (3D) chromatin architecture are profoundly remodeled during a process known as 'epigenetic reprogramming.' An understudied aspect of epigenetic reprogramming is how the 5meC flux, per se, affects the 3D genome. This is pertinent given the 5meC-sensitivity of DNA binding for a key regulator of chromosome folding: CTCF. We profiled the CTCF binding landscape using a mouse embryonic stem cell (ESC) differentiation protocol that models embryonic 5meC dynamics. Mouse ESCs lacking DNA methylation machinery are able to exit naive pluripotency, thus allowing for dissection of subtle effects of CTCF on gene expression. We performed CTCF HiChIP in both wild-type and mutant conditions to assess gained CTCF-CTCF contacts in the absence of 5meC. We performed H3K27ac HiChIP to determine the impact that ectopic CTCF binding has on cis-regulatory contacts. Using 5meC epigenome editing, we demonstrated that the methyl-mark is able to impair CTCF binding at select loci. Finally, a detailed dissection of the imprinted Zdbf2 locus showed how 5meC-antagonism of CTCF allows for proper gene regulation during differentiation. This work provides a comprehensive overview of how 5meC impacts the 3D genome in a relevant model for early embryonic events.

6.
Nucleic Acids Res ; 52(11): 6183-6200, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38613389

RESUMO

The imprinted Dlk1-Dio3 domain comprises the developmental genes Dlk1 and Rtl1, which are silenced on the maternal chromosome in different cell types. On this parental chromosome, the domain's imprinting control region activates a polycistron that produces the lncRNA Meg3 and many miRNAs (Mirg) and C/D-box snoRNAs (Rian). Although Meg3 lncRNA is nuclear and associates with the maternal chromosome, it is unknown whether it controls gene repression in cis. We created mouse embryonic stem cells (mESCs) that carry an ectopic poly(A) signal, reducing RNA levels along the polycistron, and generated Rian-/- mESCs as well. Upon ESC differentiation, we found that Meg3 lncRNA (but not Rian) is required for Dlk1 repression on the maternal chromosome. Biallelic Meg3 expression acquired through CRISPR-mediated demethylation of the paternal Meg3 promoter led to biallelic Dlk1 repression, and to loss of Rtl1 expression. lncRNA expression also correlated with DNA hypomethylation and CTCF binding at the 5'-side of Meg3. Using Capture Hi-C, we found that this creates a Topologically Associating Domain (TAD) organization that brings Meg3 close to Dlk1 on the maternal chromosome. The requirement of Meg3 for gene repression and TAD structure may explain how aberrant MEG3 expression at the human DLK1-DIO3 locus associates with imprinting disorders.


Assuntos
Proteínas de Ligação ao Cálcio , Diferenciação Celular , Impressão Genômica , RNA Longo não Codificante , Animais , Camundongos , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Metilação de DNA , Regulação da Expressão Gênica no Desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Proteínas Nucleares , Proteínas da Gravidez , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
8.
Nature ; 512(7512): 96-100, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-25043061

RESUMO

Developmental enhancers initiate transcription and are fundamental to our understanding of developmental networks, evolution and disease. Despite their importance, the properties governing enhancer-promoter interactions and their dynamics during embryogenesis remain unclear. At the ß-globin locus, enhancer-promoter interactions appear dynamic and cell-type specific, whereas at the HoxD locus they are stable and ubiquitous, being present in tissues where the target genes are not expressed. The extent to which preformed enhancer-promoter conformations exist at other, more typical, loci and how transcription is eventually triggered is unclear. Here we generated a high-resolution map of enhancer three-dimensional contacts during Drosophila embryogenesis, covering two developmental stages and tissue contexts, at unprecedented resolution. Although local regulatory interactions are common, long-range interactions are highly prevalent within the compact Drosophila genome. Each enhancer contacts multiple enhancers, and promoters with similar expression, suggesting a role in their co-regulation. Notably, most interactions appear unchanged between tissue context and across development, arising before gene activation, and are frequently associated with paused RNA polymerase. Our results indicate that the general topology governing enhancer contacts is conserved from flies to humans and suggest that transcription initiates from preformed enhancer-promoter loops through release of paused polymerase.


Assuntos
RNA Polimerases Dirigidas por DNA/metabolismo , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Desenvolvimento Embrionário/genética , Elementos Facilitadores Genéticos/genética , Regiões Promotoras Genéticas/genética , Animais , Sítios de Ligação , Cromossomos de Insetos/genética , Cromossomos de Insetos/metabolismo , Drosophila melanogaster/embriologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Loci Gênicos/genética , Genoma de Inseto/genética , Humanos , Iniciação da Transcrição Genética , Ativação Transcricional
9.
PLoS Genet ; 13(7): e1006903, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28749941

RESUMO

Developmental genes can harbour multiple transcriptional enhancers that act simultaneously or in succession to achieve robust and precise spatiotemporal expression. However, the mechanisms underlying cooperation between cis-acting elements are poorly documented, notably in vertebrates. The mouse gene Krox20 encodes a transcription factor required for the specification of two segments (rhombomeres) of the developing hindbrain. In rhombomere 3, Krox20 is subject to direct positive feedback governed by an autoregulatory enhancer, element A. In contrast, a second enhancer, element C, distant by 70 kb, is active from the initiation of transcription independent of the presence of the KROX20 protein. Here, using both enhancer knock-outs and investigations of chromatin organisation, we show that element C possesses a dual activity: besides its classical enhancer function, it is also permanently required in cis to potentiate the autoregulatory activity of element A, by increasing its chromatin accessibility. This work uncovers a novel, asymmetrical, long-range mode of cooperation between cis-acting elements that might be essential to avoid promiscuous activation of positive autoregulatory elements.


Assuntos
Proteína 1 de Resposta de Crescimento Precoce/genética , Elementos Facilitadores Genéticos , Elementos Reguladores de Transcrição/genética , Rombencéfalo/crescimento & desenvolvimento , Animais , Padronização Corporal/genética , Cromatina/genética , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Camundongos Knockout , Mutação , Rombencéfalo/metabolismo , Homologia de Sequência do Ácido Nucleico
10.
Proc Natl Acad Sci U S A ; 112(15): 4672-7, 2015 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-25825760

RESUMO

Embryogenesis requires the precise activation and repression of many transcriptional regulators. The Polycomb group proteins and the associated H3K27me3 histone mark are essential to maintain the inactive state of many of these genes. Mammalian Hox genes are targets of Polycomb proteins and form local 3D clusters centered on the H3K27me3 mark. More distal contacts have also been described, yet their selectivity, dynamics, and relation to other layers of chromatin organization remained elusive. We report that repressed Hox genes form mutual intra- and interchromosomal interactions with other genes located in strong domains labeled by H3K27me3. These interactions occur in a central and active nuclear environment that consists of the HiC compartment A, away from peripheral lamina-associated domains. Interactions are independent of nearby H3K27me3-marked loci and determined by chromosomal distance and cell-type-specific scaling factors, thus inducing a moderate reorganization during embryogenesis. These results provide a simplified view of nuclear organization whereby Polycomb proteins may have evolved to repress genes located in gene-dense regions whose position is restricted to central, active, nuclear environments.


Assuntos
Cromossomos de Mamíferos/metabolismo , Histonas/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas Nucleares/metabolismo , Animais , Células Cultivadas , Cromossomos de Mamíferos/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Histonas/genética , Proteínas de Homeodomínio/genética , Lamina Tipo B/genética , Lamina Tipo B/metabolismo , Lisina/genética , Lisina/metabolismo , Masculino , Metilação , Camundongos , Modelos Genéticos , Família Multigênica , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Ligação Proteica
11.
PLoS Biol ; 12(1): e1001773, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24465181

RESUMO

The evolution of tetrapod limbs from fish fins enabled the conquest of land by vertebrates and thus represents a key step in evolution. Despite the use of comparative gene expression analyses, critical aspects of this transformation remain controversial, in particular the origin of digits. Hoxa and Hoxd genes are essential for the specification of the different limb segments and their functional abrogation leads to large truncations of the appendages. Here we show that the selective transcription of mouse Hoxa genes in proximal and distal limbs is related to a bimodal higher order chromatin structure, similar to that reported for Hoxd genes, thus revealing a generic regulatory strategy implemented by both gene clusters during limb development. We found the same bimodal chromatin architecture in fish embryos, indicating that the regulatory mechanism used to pattern tetrapod limbs may predate the divergence between fish and tetrapods. However, when assessed in mice, both fish regulatory landscapes triggered transcription in proximal rather than distal limb territories, supporting an evolutionary scenario whereby digits arose as tetrapod novelties through genetic retrofitting of preexisting regulatory landscapes. We discuss the possibility to consider regulatory circuitries, rather than expression patterns, as essential parameters to define evolutionary synapomorphies.


Assuntos
Nadadeiras de Animais/embriologia , Extremidades/embriologia , Proteínas de Homeodomínio/genética , Tetraodontiformes/genética , Peixe-Zebra/genética , Nadadeiras de Animais/metabolismo , Animais , Evolução Biológica , Embrião de Mamíferos , Embrião não Mamífero , Extremidades/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/classificação , Camundongos , Morfogênese/genética , Família Multigênica , Filogenia
13.
Nat Struct Mol Biol ; 31(3): 404-412, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38499830

RESUMO

Cytosine DNA methylation is a highly conserved epigenetic mark in eukaryotes. Although the role of DNA methylation at gene promoters and repetitive elements has been extensively studied, the function of DNA methylation in other genomic contexts remains less clear. In the nucleus of mammalian cells, the genome is spatially organized at different levels, and strongly influences myriad genomic processes. There are a number of factors that regulate the three-dimensional (3D) organization of the genome, with the CTCF insulator protein being among the most well-characterized. Pertinently, CTCF binding has been reported as being DNA methylation-sensitive in certain contexts, perhaps most notably in the process of genomic imprinting. Therefore, it stands to reason that DNA methylation may play a broader role in the regulation of chromatin architecture. Here we summarize the current understanding that is relevant to both the mammalian DNA methylation and chromatin architecture fields and attempt to assess the extent to which DNA methylation impacts the folding of the genome. The focus is in early embryonic development and cellular transitions when the epigenome is in flux, but we also describe insights from pathological contexts, such as cancer, in which the epigenome and 3D genome organization are misregulated.


Assuntos
Metilação de DNA , Proteínas Repressoras , Animais , Proteínas Repressoras/metabolismo , Fator de Ligação a CCCTC/metabolismo , Impressão Genômica , Cromatina , Mamíferos/genética
14.
Curr Opin Struct Biol ; 81: 102622, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37302180

RESUMO

Mammalian chromosomes are organized at different length scales within the cell nucleus. Topologically Associating Domains (TADs) are structural units of 3D genome organization with functions in gene regulation, DNA replication, recombination and repair. Whereas TADs were initially interpreted as insulated domains, recent studies are revealing that these domains should be interpreted as dynamic collections of actively extruding loops. This process of loop extrusion is subsequently blocked at dedicated TAD boundaries, thereby promoting intra-domain interactions over their surroundings. In this review, we discuss how mammalian TAD structure can emerge from this dynamic process and we discuss recent evidence that TAD boundaries can have regulatory functions.


Assuntos
Núcleo Celular , Cromatina , Animais , Regulação da Expressão Gênica , Cromossomos de Mamíferos , Genoma , Mamíferos/genética
15.
Cell Rep ; 42(1): 111967, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36640345

RESUMO

Hox genes encode transcription factors that specify segmental identities along the anteroposterior body axis. These genes are organized in clusters, where their order corresponds to their activity along the body axis, a feature known as collinearity. In Drosophila, the BX-C cluster contains the three most posterior Hox genes, where their collinear activation incorporates progressive changes in histone modifications, chromatin architecture, and use of boundary elements and cis-regulatory regions. To dissect functional hierarchies, we compare chromatin organization in cell lines and larvae, with a focus on the Abd-B gene. Our work establishes the importance of the Fab-7 boundary for insulation between 3D domains carrying different histone modifications. Interestingly, we detect a non-canonical inversion of collinear chromatin dynamics at Abd-B, with the domain of active histone modifications progressively decreasing in size. This dynamic chromatin organization differentially activates the alternative promoters of the Abd-B gene, thereby expanding the possibilities for fine-tuning of transcriptional output.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas de Homeodomínio/metabolismo , Regiões Promotoras Genéticas/genética , Sequências Reguladoras de Ácido Nucleico , Genes Homeobox , Cromatina , Regulação da Expressão Gênica no Desenvolvimento
16.
Nat Commun ; 14(1): 5615, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37699887

RESUMO

Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites of the CTCF insulator protein. Here we determine how this clustering of CTCF binding contributes to the blocking of loop extrusion and the insulation between TADs. We identify enrichment of three features of CTCF binding at strong TAD boundaries, consisting of strongly bound and closely spaced CTCF binding peaks, with a further enrichment of DNA-binding motifs within these peaks. Using multi-contact Nano-C analysis in cells with normal and perturbed CTCF binding, we establish that individual CTCF binding sites contribute to the blocking of loop extrusion, but in an incomplete manner. When clustered, individual CTCF binding sites thus create a stepwise insulation between neighboring TADs. Based on these results, we propose a model whereby multiple instances of temporal loop extrusion blocking create strong insulation between TADs.


Assuntos
Sítios de Ligação , Fator de Ligação a CCCTC/genética , Análise por Conglomerados , Domínios Proteicos
17.
Cell Genom ; 2(4): 100121, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-36776526

RESUMO

Hi-C is a powerful technology for exploring 3D genome organization on a genome-wide scale, yet it can be financially and computationally challenging. In a recent issue of Molecular Cell, Wei et al.1 introduce HiCAR, which simplifies Hi-C by targeting the 3D interactions of accessible regions only.

18.
Comput Struct Biotechnol J ; 20: 2685-2698, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685367

RESUMO

The emergence and progression of cancers is accompanied by a dysregulation of transcriptional programs. The three-dimensional (3D) organization of the human genome has emerged as an important multi-level mediator of gene transcription and regulation. In cancer cells, this organization can be restructured, providing a framework for the deregulation of gene activity. The CTCF protein, initially identified as the product from a tumor suppressor gene, is a jack-of-all-trades for the formation of 3D genome organization in normal cells. Here, we summarize how CTCF is involved in the multi-level organization of the human genome and we discuss emerging insights into how perturbed CTCF function and DNA binding causes the activation of oncogenes in cancer cells, mostly through a process of enhancer hijacking. Moreover, we highlight non-canonical functions of CTCF that can be relevant for the emergence of cancers as well. Finally, we provide guidelines for the computational identification of perturbed CTCF binding and reorganized 3D genome structure in cancer cells.

19.
Methods Mol Biol ; 2532: 15-33, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35867243

RESUMO

Chromosome conformation capture techniques are a set of methods used to determine 3D genome organization through the capture and identification of physical contacts between pairs of genomic loci. Among them, 4C-seq (circular chromosome conformation capture coupled to high-throughput sequencing) allows for the identification and quantification of the sequences interacting with a preselected locus of interest. 4C-seq has been widely used in the literature, mainly to study chromatin loops between enhancers and promoters or between CTCF binding sites and to identify chromatin domain boundaries. As 3D-contacts may be established in an allele-specific manner, we describe an up-to-date allele-specific 4C-seq protocol, starting from the selection of allele-specific viewpoints to Illumina sequencing. This protocol has mainly been optimized for cultured mammalian cells, but can be adapted for other cell types with relatively minor changes in initial steps.


Assuntos
Cromatina , Cromossomos , Alelos , Animais , Cromatina/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mamíferos/genética
20.
Nat Commun ; 13(1): 1039, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35210422

RESUMO

The contractile properties of adult myofibers are shaped by their Myosin heavy chain isoform content. Here, we identify by snATAC-seq a 42 kb super-enhancer at the locus regrouping the fast Myosin genes. By 4C-seq we show that active fast Myosin promoters interact with this super-enhancer by DNA looping, leading to the activation of a single promoter per nucleus. A rainbow mouse transgenic model of the locus including the super-enhancer recapitulates the endogenous spatio-temporal expression of adult fast Myosin genes. In situ deletion of the super-enhancer by CRISPR/Cas9 editing demonstrates its major role in the control of associated fast Myosin genes, and deletion of two fast Myosin genes at the locus reveals an active competition of the promoters for the shared super-enhancer. Last, by disrupting the organization of fast Myosin, we uncover positional heterogeneity within limb skeletal muscles that may underlie selective muscle susceptibility to damage in certain myopathies.


Assuntos
Fibras Musculares Esqueléticas , Miosinas , Animais , Camundongos , Camundongos Transgênicos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Miosinas/genética , Miosinas/metabolismo , Fenótipo
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