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1.
Methods Mol Biol ; 2566: 215-223, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36152254

RESUMO

The chromatin dispersion test (CDT) is based on the removal of nuclear proteins under the assumption that cells with fragmented DNA produce a typical halo of circular DNA loops, which is absent in cells with non-fragmented DNA. This method represents a simple, rapid, accurate, highly reproducible, and inexpensive technique to assess nuclear DNA damage in somatic cells. The visualization of DNA damage and the capacity of the test to provide a threshold value to discriminate between high and low levels of cervical lesions would aid in determining the malignant transformation. All of these advantages associated with the CDT protocol could promote this technique as a tool for the quick and reliable diagnosis of cervical epithelial disorders, even at primary-care centers.


Assuntos
Cromatina , Espermatozoides , Animais , Cromatina/genética , Cromatina/metabolismo , DNA/metabolismo , Dano ao DNA , Fragmentação do DNA , DNA Circular/metabolismo , Células Epiteliais/metabolismo , Equidae , Masculino , Proteínas Nucleares/metabolismo , Espermatozoides/metabolismo
2.
Methods Mol Biol ; 2519: 127-140, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36066718

RESUMO

Hi-C is a method that analyzes genome-wide chromatin structure using next-generation sequencer. Chromatin structure is crucial for regulating transcription or replication, and Hi-C has revealed the hierarchical chromatin structures, such as loop, domain , and compartment structures. Aberrant alteration of these structures causes disease, and a number of structural aberrations in cancer cells have been reported recently. Besides, Hi-C can identify chromosome rearrangements that frequently occurred in cancer. Therefore, Hi-C is a powerful technique to analyze epigenomic and genomic aberrations in tumorigenesis. Here we will introduce the basic protocol of Hi-C in experimental and analytical aspects.


Assuntos
Cromatina , Neoplasias , Cromatina/genética , Cromossomos , Genoma , Genômica/métodos , Humanos , Neoplasias/genética
3.
Methods Mol Biol ; 2519: 163-185, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36066721

RESUMO

Posttranslational modifications of histone are intimately related to chromatin/chromosome-mediated cellular events. Among all, the roles of histone modifications including acetylation, methylation, ubiquitination, and SUMOylation of lysine or arginine residue of nucleosome core histones in gene expression have been intensively studied. Genome-wide profiles of histone modification marks revealed their combinatorial organization in the functional features of chromatin. Analysis of histone modification by chromatin immunoprecipitation (ChIP) is one of the standard assays to examine chromatin states. Although high-throughput sequencing analysis (ChIP-seq) is now widely conducted, classical ChIP-qPCR analysis has advantages in investigation of multiple histone modification marks at a target site simply through the use of relatively small numbers of cells. Since ChIP-qPCR is devoid of biases caused by overamplification and inaccurate mapping of sequencing reads, it is a more reliable quantification method than genome-wide ChIP-seq especially for analyses of the low-mappability regions, which harbor many repetitive sequences and/or highly homologous segmental multiplications as found in gene clusters. We have recently analyzed histone H3 and H4 modifications of the Zscan4 family gene loci in an 880 kb gene cluster and found that the atypical enhancer-like structure is formed upon derepression of Zscan4. In this chapter, we describe the detailed protocols for histone modification ChIP-assay of repeat-enriched gene cluster regions. The protocol here we applied to mouse ES cells, but the protocol is perfectly applicable to human cultured cells and specimens.


Assuntos
Código das Histonas , Histonas , Animais , Cromatina/genética , Imunoprecipitação da Cromatina/métodos , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Processamento de Proteína Pós-Traducional
4.
Methods Mol Biol ; 2563: 117-133, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36227470

RESUMO

A vast number of intracellular membraneless bodies also known as biomolecular condensates form through a liquid-liquid phase separation (LLPS) of biomolecules. To date, phase separation has been identified as the main driving force for a membraneless organelles such as nucleoli, Cajal bodies, stress granules, and chromatin compartments. Recently, the protein-RNA condensation is receiving increased attention, because it is closely related to the biological function of cells such as transcription, translation, and RNA metabolism. Despite the multidisciplinary efforts put forth to study the biophysical properties of protein-RNA condensates, there are many fundamental unanswered questions regarding the mechanism of formation and regulation of protein-RNA condensates in eukaryotic cells. Major challenges in studying protein-RNA condensation stem from (i) the molecular heterogeneity and conformational flexibility of RNA and protein chains and (ii) the nonequilibrium nature of transcription and cellular environment. Computer simulations, bioinformatics, and mathematical models are uniquely positioned for shedding light on the microscopic nature of protein-RNA phase separation. To this end, there is an urgent need for innovative models with the right spatiotemporal resolution for confronting the experimental observables in a comprehensive and physics-based manner. In this chapter, we will summarize the currently emerging research efforts, which employ atomistic and coarse-grained molecular models and field theoretical models to understand equilibrium and nonequilibrium aspects of protein-RNA condensation.


Assuntos
Organelas , RNA , Nucléolo Celular/metabolismo , Cromatina/metabolismo , Corpos Enovelados/metabolismo , Organelas/metabolismo , RNA/metabolismo
5.
Semin Cell Dev Biol ; 135: 50-58, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35221208

RESUMO

Exchanging core histones in the nucleosome for paralogous variants can have important functional ramifications. Many of these variants, and their physiological roles, have been characterized in exquisite detail in model eukaryotes, including humans. In comparison, our knowledge of histone biology in archaea remains rudimentary. This is true in particular for our knowledge of histone variants. Many archaea encode several histone genes that differ in sequence, but do these paralogs make distinct, adaptive contributions to genome organization and regulation in a manner comparable to eukaryotes? Below, we review what we know about histone variants in archaea at the level of structure, regulation, and evolution. In all areas, our knowledge pales when compared to the wealth of insight that has been gathered for eukaryotes. Recent findings, however, provide tantalizing glimpses into a rich and largely undiscovered country that is at times familiar and eukaryote-like and at times strange and uniquely archaeal. We sketch a preliminary roadmap for further exploration of this country; an undertaking that may ultimately shed light not only on chromatin biology in archaea but also on the origin of histone-based chromatin in eukaryotes.


Assuntos
Archaea , Histonas , Humanos , Histonas/genética , Archaea/genética , Archaea/química , Nucleossomos/genética , Cromatina , Células Eucarióticas
6.
Semin Cell Dev Biol ; 135: 3-12, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35365397

RESUMO

Chromatin, the functional organization of DNA with histone proteins in eukaryotic nuclei, is the tightly-regulated template for several biological processes, such as transcription, replication, DNA damage repair, chromosome stability and sister chromatid segregation. In order to achieve a reversible control of local chromatin structure and DNA accessibility, various interconnected mechanisms have evolved. One of such processes includes the deposition of functionally-diverse variants of histone proteins into nucleosomes, the building blocks of chromatin. Among core histones, the family of H2A histone variants exhibits the largest number of members and highest sequence-divergence. In this short review, we report and discuss recent discoveries concerning the biological functions of the animal histone variants H2A.B, H2A.X and H2A.Z and how dysregulation or mutation of the latter impacts the development of disease.


Assuntos
Histonas , Nucleossomos , Animais , Histonas/genética , Histonas/metabolismo , Nucleossomos/genética , Cromatina/genética , Reparo do DNA/genética , DNA/genética
7.
Semin Cell Dev Biol ; 135: 24-34, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35422390

RESUMO

Centromeres are highly specialised chromosome domains defined by the presence of an epigenetic mark, the specific histone H3 variant called CENP-A (centromere protein A). They constitute the genomic regions on which kinetochores form and when defective cause segregation defects that can lead to aneuploidy and cancer. Here, we discuss how CENP-A is established and maintained to propagate centromere identity while subjected to dynamic chromatin remodelling during essential cellular processes like DNA repair, replication, and transcription. We highlight parallels and identify conserved mechanisms between different model organism with a particular focus on 1) the establishment of CENP-A at centromeres, 2) CENP-A maintenance during transcription and replication, and 3) the mechanisms that help preventing CENP-A localization at non-centromeric sites. We then give examples of how timely loading of new CENP-A to the centromere, maintenance of old CENP-A during S-phase and transcription, and removal of CENP-A at non-centromeric sites are coordinated and controlled by an intricate network of factors whose identity is slowly being unravelled.


Assuntos
Cromatina , Histonas , Histonas/genética , Histonas/metabolismo , Proteína Centromérica A/genética , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Centrômero/metabolismo , Proteínas de Ciclo Celular/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo
8.
Semin Cell Dev Biol ; 135: 43-49, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35422391

RESUMO

The replacement of replication-coupled histones with non-canonical histone variants provides chromatin with additional properties and contributes to the plasticity of the epigenome. MacroH2A histone variants are counterparts of the replication-coupled histone H2A. They are characterized by a unique tripartite structure, consisting of a histone fold, an unstructured linker, and a globular macrodomain. MacroH2A1.1 and macroH2A1.2 are the result of alternative splicing of the MACROH2A1 gene and can have opposing biological functions. Here, we discuss the structural differences between the macrodomains of the two isoforms, resulting in differential ligand binding. We further discuss how this modulates gene regulation by the two isoforms, in cases resulting in opposing role of macroH2A1.1 and macroH2A1.2 in development and differentiation. Finally, we share recent insight in the evolution of macroH2As. Taken together, in this review, we aim to discuss in unprecedented detail distinct properties and functions of the fascinating macroH2A1 splice isoforms.


Assuntos
Cromatina , Histonas , Histonas/genética , Histonas/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Regulação da Expressão Gênica
9.
Semin Cell Dev Biol ; 135: 13-23, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35595602

RESUMO

Histone variant H3.3 is incorporated into chromatin throughout the cell cycle and even in non-cycling cells. This histone variant marks actively transcribed chromatin regions with high nucleosome turnover, as well as silent pericentric and telomeric repetitive regions. In the past few years, significant progress has been made in our understanding of mechanisms involved in the transcription-coupled deposition of H3.3. Here we review how, during transcription, new H3.3 deposition intermingles with the fate of the old H3.3 variant and its recycling. First, we describe pathways enabling the incorporation of newly synthesized vs old H3.3 histones in the context of transcription. We then review the current knowledge concerning differences between these two H3.3 populations, focusing on their PTMs composition. Finally, we discuss the implications of H3.3 recycling for the maintenance of the transcriptional state and underline the emerging importance of H3.3 as a potent epigenetic regulator for both maintaining and switching a transcriptional state.


Assuntos
Cromatina , Histonas , Histonas/genética , Histonas/metabolismo , Cromatina/genética , Nucleossomos/genética
11.
Methods Mol Biol ; 2581: 285-293, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36413325

RESUMO

Chromatin enrichment for proteomics (ChEP) is a technique that allows for unbiased proteomic profiling of the chromatin landscape using mass spectrometry. While the method has been successfully employed to survey chromatin-associated proteins in various organisms and cell types, ChEP has not yet been applied to plant materials. Here, we describe a detailed ChEP protocol which has been modified for plants and designated ChEP-P (ChEP in plants). The protocol outlined here includes all necessary steps to perform a label-free quantitative ChEP-P experiment, supporting the identification of more than 3500 proteins in Arabidopsis thaliana.


Assuntos
Arabidopsis , Proteômica , Proteômica/métodos , Cromatina/genética , Plantas , Espectrometria de Massas , Arabidopsis/genética
12.
Semin Cell Dev Biol ; 135: 93-101, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35249811

RESUMO

Variants of the histone H2A occupy distinct locations in the genome. There is relatively little known about the mechanisms responsible for deposition of specific H2A variants. Notable exceptions are chromatin remodelers that control the dynamics of H2A.Z at promoters. Here we review the steps that identified the role of a specific class of chromatin remodelers, including LSH and DDM1 that deposit the variants macroH2A in mammals and H2A.W in plants, respectively. The function of these remodelers in heterochromatin is discussed together with their multiple roles in genome stability.


Assuntos
Heterocromatina , Histonas , Animais , Histonas/genética , Histonas/metabolismo , Heterocromatina/genética , Cromatina , Regiões Promotoras Genéticas , Mamíferos/genética , Biologia , Nucleossomos
13.
Semin Cell Dev Biol ; 135: 73-84, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35277331

RESUMO

Post-translational modifications (PTMs) of histones play a key role in DNA-based processes and contribute to cell differentiation and gene function by adding an extra layer of regulation. Variations in histone sequences within each family of histones expands the chromatin repertoire and provide further mechanisms for regulation and signaling. While variants are known to be present in certain genomic loci and carry out important functions, much remains unknown about variant-specific PTMs and their role in regulating chromatin. This ambiguity is in part due to the limited technologies and appropriate reagents to identify and quantitate variant-specific PTMs. Nonetheless, histone variants are an integral portion of the chromatin system and the understanding of their modifications and resolving how PTMs function differently on specific variants is paramount to the advancement of the field. Here we review the current knowledge on post-translational modifications specific to histone variants, with an emphasis on well-characterized PTMs of known function. While not every possible PTM is addressed, we present key variant-specific PTMs and what is known about their function and mechanisms in convenient reference tables.


Assuntos
Histonas , Processamento de Proteína Pós-Traducional , Histonas/genética , Histonas/metabolismo , Processamento de Proteína Pós-Traducional/genética , Cromatina/genética , DNA/genética
14.
Semin Cell Dev Biol ; 135: 59-72, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35331626

RESUMO

Histone variants represent chromatin components that diversify the structure and function of the genome. The variants of H2A, primarily H2A.X, H2A.Z and macroH2A, are well-established participants in DNA damage response (DDR) pathways, which function to protect the integrity of the genome. Through their deposition, post-translational modifications and unique protein interaction networks, these variants guard DNA from endogenous threats including replication stress and genome fragility as well as from DNA lesions inflicted by exogenous sources. A growing body of work is now providing a clearer picture on the involvement and mechanistic basis of H2A variant contribution to genome integrity. Beyond their well-documented role in gene regulation, we review here how histone H2A variants promote genome stability and how alterations in these pathways contribute to human diseases including cancer.


Assuntos
Cromatina , Histonas , Humanos , Histonas/genética , Histonas/metabolismo , Cromatina/genética , Genoma , Processamento de Proteína Pós-Traducional/genética , DNA/genética
15.
Semin Cell Dev Biol ; 135: 85-92, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35474148

RESUMO

The histone variant H2A.Z plays a critical role in chromatin-based processes such as transcription, replication, and repair in eukaryotes. Although many H2A.Z-associated processes and features are conserved in plants and animals, a distinguishing feature of plant chromatin is the enrichment of H2A.Z in the bodies of genes that exhibit dynamic expression, particularly in response to differentiation and the environment. Recent work sheds new light on the plant machinery that enables dynamic changes in H2A.Z enrichment and identifies additional chromatin-based pathways that contribute to transcriptional properties of H2A.Z-enriched chromatin. In particular, analysis of a variety of responsive loci reveals a repressive role for H2A.Z in expression of responsive genes and identifies roles for SWR1 and INO80 chromatin remodelers in enabling dynamic regulation of H2A.Z levels and transcription. These studies lay the groundwork for understanding how this ancient histone variant is harnessed by plants to enable responsive and dynamic gene expression (Graphical Abstract).


Assuntos
Histonas , Nucleossomos , Animais , Histonas/genética , Histonas/metabolismo , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Plantas/genética , Plantas/metabolismo
16.
Methods Mol Biol ; 2603: 209-218, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36370282

RESUMO

DNA replication is a highly complex process that achieves the faithful transmission of genetic information from parent to progeny. Recruitment of DNA replication proteins to DNA is dynamically regulated during the cell cycle and in response to replication stresses. For a large-scale analysis of DNA replication proteins, I established a method for analysis of chromatin-bound proteins by SILAC (stable isotope labeling by amino acids in cell culture)-based quantitative proteomics. Here I describe a detailed methodology for SILAC labeling of budding yeast Saccharomyces cerevisiae, then nuclear isolation and chromatin preparation from synchronized yeast cells, prior to quantitative proteomic analysis of DNA replication proteins.


Assuntos
Proteômica , Saccharomyces cerevisiae , Proteômica/métodos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Cromatina/genética , Cromatina/metabolismo , Proteínas Fúngicas/metabolismo , Marcação por Isótopo/métodos , Replicação do DNA
17.
Adv Neurobiol ; 29: 281-304, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36255679

RESUMO

Gangliosides are sialylated glycosphingolipids (GSLs) with essential but enigmatic functions in brain activities and neural stem cell (NSC) maintenance. Our group has pioneered research on the importance of gangliosides for growth factor receptor signaling and epigenetic regulation of NSC activity and differentiation. The primary localization of gangliosides is on cell-surface microdomains and the drastic dose and composition changes during neural differentiation strongly suggest that they are not only important as biomarkers, but also are involved in modulating NSC fate determination. Ganglioside GD3 is the predominant species in NSCs and GD3-synthase knockout (GD3S-KO) revealed reduction of postnatal NSC pools with severe behavioral deficits. Exogenous administration of GD3 significantly restored the NSC pools and enhanced the stemness of NSCs with multipotency and self-renewal. Since morphological changes during neurogenesis require a huge amount of energy, mitochondrial functions are vital for neurogenesis. We discovered that a mitochondrial fission protein, the dynamin-related protein-1 (Drp1), as a novel GD3-binding protein, and GD3 regulates mitochondrial dynamics. Furthermore, we discovered that GM1 ganglioside promotes neuronal differentiation by an epigenetic regulatory mechanism. Nuclear GM1 binds with acetylated histones on the promoters of N-acetylgalactosaminyltransferase (GalNAcT; GM2 synthase) as well as on the NeuroD1 genes in differentiated neurons. In addition, epigenetic activation of the GalNAcT gene was detected as accompanied by an apparent induction of neuronal differentiation in NSCs responding to an exogenous supplement of GM1. GM1 is indeed localized in the nucleus where it can interact with transcriptionally active histones. Interestingly, GM1 could induce epigenetic activation of the tyrosine hydroxylase (TH) gene, with recruitment of nuclear receptor related 1 (Nurr1, also known as NR4A2), a dopaminergic neuron-associated transcription factor, to the TH promoter region. In this way, GM1 epigenetically regulates dopaminergic neuron specific gene expression. GM1 interacts with active chromatin via acetylated histones to recruit transcription factors at the nuclear periphery, resulting in changes in gene expression for neuronal differentiation. The significance is that multifunctional gangliosides modulate lipid microdomains to regulate functions of important molecules on multiple sites: the plasma membrane, mitochondrial membrane, and nuclear membrane. Versatile gangliosides could regulate functional neurons as well as sustain NSC functions via modulating protein and gene activities on ganglioside microdomains.


Assuntos
Gangliosídeo G(M1) , N-Acetilgalactosaminiltransferases , Humanos , Gangliosídeo G(M1)/metabolismo , Epigênese Genética , Histonas/genética , Histonas/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Gangliosídeos/genética , Gangliosídeos/metabolismo , Neurônios/metabolismo , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Glicoesfingolipídeos/metabolismo , Membranas Intracelulares/metabolismo , Biomarcadores/metabolismo , Cromatina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Theriogenology ; 195: 31-39, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36279698

RESUMO

Lyophilisation is an alternative method for sperm preservation. The aim of this study was to evaluate the effects of freeze-thawing (F/T) and freeze-drying (F/D) on the quality of epididymal goat sperm. Sperm from each region of the epididymis (caput, corpus and cauda) were collected and evaluated for the expression of phospholipase C zeta (PLC-ζ), protamine 1 (PRM1), transition protein 1 (TNP1) and 2 (TNP2). The effects of F/T and F/D on sperm quality in terms of PLC-ζ expression, chromatin stability (Chromomycin A3; CMA3) and DNA integrity were examined. The fertilising ability after intracytoplasmic sperm injection (ICSI) was also tested. Fresh sperm existed PLC-ζ, PRM1, TNP1 and TNP2, irrespective of the regions of the epididymis. However, different patterns of PLC-ζ expression were found. Although PRM1, TNP1, TNP2 were still expressed after F/T or F/D, only F/T could preserve the presence of PLC-ζ. For fresh sperm, caput epididymal sperm had the lowest evidence of chromatin stability when compared to sperm harvested from other regions of the epididymis. The F/T and F/D further increased the numbers of CMA3-positive sperm (P < 0.001). In all cases, no CMA3 staining was observed in caudal epididymal sperm. The caudal epididymal sperm had significantly greater proportions of sperm with intact DNA compared with caput and corpus epididymal sperm, especially when F/T and F/D were performed. The fertilisation rates of F/D sperm tended to decrease when compared with F/T sperm (4.2 ± 3.2 vs. 13.6 ± 9.0, P = 0.08). It is concluded that the sperm recovered from the caudal epididymis is suitable for freezing and lyophilisation. However, poor fertilisation rates of F/D sperm were coincidently observed, with a deficit demonstration of PLC-ζ.


Assuntos
Epididimo , Cabras , Masculino , Animais , Sêmen , Espermatozoides , Cromatina/metabolismo
19.
Methods Mol Biol ; 2599: 99-111, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36427145

RESUMO

Cleavage under targets and release using nuclease (CUT & RUN) is an innovative method to profile histone modifications and chromatin-bound proteins genome-wide. CUT & RUN offers two distinct advantages of requiring much fewer cells and providing strong signal-to-noise ratios in deep-sequencing data. Here, we describe a workflow starting from dissociation and sorting of mouse embryonic brains, CUT & RUN, and DNA library preparation to deep sequencing. With our workflow, researchers can obtain high-quality sequencing data to profile histones and chromatin-associated proteins by using as few as 100,000 neural progenitor cells (NPCs).


Assuntos
Cromatina , Células-Tronco Neurais , Camundongos , Animais , Cromatina/genética , Endonucleases/genética , Células-Tronco Neurais/metabolismo , Histonas/metabolismo , Código das Histonas
20.
Methods Mol Biol ; 2599: 59-68, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36427143

RESUMO

Genomic DNA wraps around core histones to form nucleosomes, which provides steric constraints on how transcription factors (TFs) can interact with gene regulatory sequences. It is increasingly apparent that well-positioned, accessible nucleosomes are an inherent feature of active enhancers and can facilitate cooperative TF binding, referred to as nucleosome-mediated cooperativity. Thus, profiling chromatin and nucleosome properties (accessibility, positioning, and occupancy) on the genome is crucial to understand cell-type-specific gene regulation. Here we describe a simplified protocol to profile accessible nucleosomes in the mammalian genome using low-level and high-level micrococcal nuclease (MNase) digestion followed by genome-wide sequencing.


Assuntos
Cromatina , Nucleossomos , Animais , Nucleossomos/genética , Cromatina/genética , Nuclease do Micrococo/metabolismo , Genoma , Histonas/genética , Histonas/metabolismo , Mamíferos/genética , Mamíferos/metabolismo
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