RESUMO
Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes1,2, underscoring the conserved metabolic benefits of oestrogen that inevitably decrease with age. In rodents, the preovulatory surge in 17ß-oestradiol (E2) temporarily increases energy expenditure to coordinate increased physical activity with peak sexual receptivity. Here we report that a subset of oestrogen-sensitive neurons in the ventrolateral ventromedial hypothalamic nucleus (VMHvl)3-7 projects to arousal centres in the hippocampus and hindbrain, and enables oestrogen to rebalance energy allocation in female mice. Surges in E2 increase melanocortin-4 receptor (MC4R) signalling in these VMHvl neurons by directly recruiting oestrogen receptor-α (ERα) to the Mc4r gene. Sedentary behaviour and obesity in oestrogen-depleted female mice were reversed after chemogenetic stimulation of VMHvl neurons expressing both MC4R and ERα. Similarly, a long-term increase in physical activity is observed after CRISPR-mediated activation of this node. These data extend the effect of MC4R signalling - the most common cause of monogenic human obesity8 - beyond the regulation of food intake and rationalize reported sex differences in melanocortin signalling, including greater disease severity of MC4R insufficiency in women9. This hormone-dependent node illuminates the power of oestrogen during the reproductive cycle in motivating behaviour and maintaining an active lifestyle in women.
Assuntos
Encéfalo/fisiologia , Estrogênios/metabolismo , Esforço Físico/fisiologia , Receptor Tipo 4 de Melanocortina/metabolismo , Transdução de Sinais , Animais , Sistemas CRISPR-Cas , Metabolismo Energético , Receptor alfa de Estrogênio/metabolismo , Estrogênios/deficiência , Feminino , Edição de Genes , Hipocampo/metabolismo , Masculino , Melanocortinas/metabolismo , Camundongos , Neurônios/metabolismo , Obesidade/metabolismo , Rombencéfalo/metabolismo , Comportamento Sedentário , Caracteres Sexuais , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/fisiologiaRESUMO
DNA strand asymmetries can have a major effect on several biological functions, including replication, transcription and transcription factor binding. As such, DNA strand asymmetries and mutational strand bias can provide information about biological function. However, a versatile tool to explore this does not exist. Here, we present Asymmetron, a user-friendly computational tool that performs statistical analysis and visualizations for the evaluation of strand asymmetries. Asymmetron takes as input DNA features provided with strand annotation and outputs strand asymmetries for consecutive occurrences of a single DNA feature or between pairs of features. We illustrate the use of Asymmetron by identifying transcriptional and replicative strand asymmetries of germline structural variant breakpoints. We also show that the orientation of the binding sites of 45% of human transcription factors analyzed have a significant DNA strand bias in transcribed regions, that is also corroborated in ChIP-seq analyses, and is likely associated with transcription. In summary, we provide a novel tool to assess DNA strand asymmetries and show how it can be used to derive new insights across a variety of biological disciplines.
Assuntos
Biologia Computacional/métodos , Replicação do DNA/genética , DNA/genética , Mutação , Transcrição Gênica/genética , Células A549 , Algoritmos , Linhagem Celular Transformada , DNA/química , DNA/metabolismo , Células Hep G2 , Humanos , Células K562 , Células MCF-7 , Modelos Genéticos , Ligação Proteica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10-25). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10-14), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin-melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function.
Assuntos
Disfunção Erétil/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Idoso , Alelos , Índice de Massa Corporal , Estudos de Casos e Controles , Cromossomos Humanos Par 6/genética , Estudos de Coortes , Humanos , Leptina/genética , Masculino , Melanocortinas/genética , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genéticaRESUMO
The organization and folding of chromatin within the nucleus can determine the outcome of gene expression. Recent technological advancements have enabled us to study chromatin interactions in a genome-wide manner at high resolution. These studies have increased our understanding of the hierarchy and dynamics of chromatin domains that facilitate cognate enhancer-promoter looping, defining the transcriptional program of different cell types. In this review, we focus on vertebrate chromatin long-range interactions as they relate to transcriptional regulation. In addition, we describe how the alteration of boundaries that mark discrete regions in the genome with high interaction frequencies within them, called topological associated domains (TADs), could lead to various phenotypes, including human diseases, which we term as "TADopathies."
Assuntos
Montagem e Desmontagem da Cromatina/genética , Elementos Facilitadores Genéticos , Regiões Promotoras Genéticas , Transcrição Gênica , Animais , Cromatina/genética , Regulação da Expressão Gênica , Humanos , MamíferosRESUMO
The organization of eukaryotic genome into chromatin within the nucleus eventually dictates the cell type specific expression pattern of genes. This higher order of chromatin organization is established during development and dynamically maintained throughout the life span. Developmental mechanisms are conserved in bilaterians and hence they have body plan in common, which is achieved by regulatory networks controlling cell type specific gene expression. Homeotic genes are conserved in metazoans and are crucial for animal development as they specify cell type identity along the anterior-posterior body axis. Hox genes are the best studied in the context of epigenetic regulation that has led to significant understanding of the organismal development. Epigenome specific regulation is brought about by conserved chromatin modulating factors like PcG/trxG proteins during development and differentiation. Here we discuss the conserved epigenetic mechanisms relevant to homeotic gene regulation in metazoans.
Assuntos
Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Animais , Montagem e Desmontagem da Cromatina , Genótipo , Humanos , Morfogênese/genética , Mutação , Fenótipo , Elementos Reguladores de Transcrição , Transcrição GênicaRESUMO
The human genome contains millions of retrotransposons, several of which could become active due to somatic mutations having phenotypic consequences, including disease. However, it is not thoroughly understood how nucleotide changes in retrotransposons affect their jumping activity. Here, we developed a novel massively parallel jumping assay (MPJA) that can test the jumping potential of thousands of transposons en masse. We generated nucleotide variant library of selected four Alu retrotransposons containing 165,087 different haplotypes and tested them for their jumping ability using MPJA. We found 66,821 unique jumping haplotypes, allowing us to pinpoint domains and variants vital for transposition. Mapping these variants to the Alu-RNA secondary structure revealed stem-loop features that contribute to jumping potential. Combined, our work provides a novel high-throughput assay that assesses the ability of retrotransposons to jump and identifies nucleotide changes that have the potential to reactivate them in the human genome.
RESUMO
Homeotic genes and their genomic organization show remarkable conservation across bilaterians. Consequently, the regulatory mechanisms, which control hox gene expression, are also highly conserved. The crucial presence of conserved GA rich motifs between Hox genes has been previously observed but what factor binds to these is still unknown. Previously we have reported that the vertebrate homologue of Drosophila Trl-GAF preferentially binds to GA rich regions in Evx2-hoxd13 intergenic region of vertebrate HoxD cluster. In this study, we show that the vertebrate-GAF (v-GAF) binds at known cis-regulatory elements in the HoxD complex of zebrafish and mouse. We further used morpholino based knockdown and CRISPR-cas9 knockout technique to deplete the v-GAF in zebrafish. We checked expression of the HoxD genes and found gain of the HoxD4 gene in GAF knockout embryos. Further, we partially rescued the morphological phenotypes in GAF depleted embryos by providing GAF mRNA. Our results show that GAF binds at intergenic regions of the HoxD complex and is important for maintaining the spatial domains of HoxD4 expression during embryonic development.
Assuntos
Desenvolvimento Embrionário , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Padronização Corporal/genética , Desenvolvimento Embrionário/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
Experimental models of the central nervous system (CNS) are imperative for developmental and pathophysiological studies of neurological diseases. Among these models, three-dimensional (3D) induced pluripotent stem cell (iPSC)-derived brain organoid models have been successful in mitigating some of the drawbacks of 2D models; however, they are plagued by high organoid-to-organoid variability, making it difficult to compare specific gene regulatory pathways across 3D organoids with those of the native brain. Single-cell RNA sequencing (scRNA-seq) transcriptome datasets have recently emerged as powerful tools to perform integrative analyses and compare variability across organoids. However, transcriptome studies focusing on late-stage neural functionality development have been underexplored. Here, we combine and analyze 8 brain organoid transcriptome databases to study the correlation between differentiation protocols and their resulting cellular functionality across various 3D organoid and exogenous brain models. We utilize dimensionality reduction methods including principal component analysis (PCA) and uniform manifold approximation projection (UMAP) to identify and visualize cellular diversity among 3D models and subsequently use gene set enrichment analysis (GSEA) and developmental trajectory inference to quantify neuronal behaviors such as axon guidance, synapse transmission and action potential. We showed high similarity in cellular composition, cellular differentiation pathways and expression of functional genes in human brain organoids during induction and differentiation phases, i.e., up to 3 months in culture. However, during the maturation phase, i.e., 6-month timepoint, we observed significant developmental deficits and depletion of neuronal and astrocytes functional genes as indicated by our GSEA results. Our results caution against use of organoids to model pathophysiology and drug response at this advanced time point and provide insights to tune in vitro iPSC differentiation protocols to achieve desired neuronal functionality and improve current protocols.
Assuntos
Encéfalo/metabolismo , Diferenciação Celular/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Biológicos , Organoides/metabolismo , Transcriptoma/genética , Encéfalo/embriologia , Bases de Dados Genéticas , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Neurônios/citologia , Neurônios/metabolismo , Reprodução , Análise de Sequência de RNA , Transdução de Sinais/genética , Análise de Célula ÚnicaRESUMO
Over a thousand diseases are caused by mutations that alter gene expression levels. The potential of nuclease-deficient zinc fingers, TALEs or CRISPR fusion systems to treat these diseases by modulating gene expression has recently emerged. These systems can be applied to modify the activity of gene-regulatory elements - promoters, enhancers, silencers and insulators, subsequently changing their target gene expression levels to achieve therapeutic benefits - an approach termed cis-regulation therapy (CRT). Here, we review emerging CRT technologies and assess their therapeutic potential for treating a wide range of diseases caused by abnormal gene dosage. The challenges facing the translation of CRT into the clinic are discussed.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Doenças Genéticas Inatas/tratamento farmacológico , Preparações Farmacêuticas/administração & dosagem , Animais , Sistemas CRISPR-Cas/efeitos dos fármacos , Sistemas CRISPR-Cas/genética , Regulação da Expressão Gênica/genética , Doenças Genéticas Inatas/genética , Humanos , Mutação/efeitos dos fármacos , Mutação/genéticaRESUMO
A crucial step in creating reliablein vitroplatforms for neural development and disorder studies is the reproduction of the multicellular three-dimensional (3D) brain microenvironment and the capturing of cell-cell interactions within the model. The power of self-organization of diverse cell types into brain spheroids could be harnessed to study mechanisms underlying brain development trajectory and diseases. A challenge of current 3D organoid and spheroid models grown in petri-dishes is the lack of control over cellular localization and diversity. To overcome this limitation, neural spheroids can be patterned into customizable 3D structures using microfabrication. We developed a 3D brain-like co-culture construct using embedded 3D bioprinting as a flexible solution for composing heterogenous neural populations with neurospheroids and glia. Specifically, neurospheroid-laden free-standing 3D structures were fabricated in an engineered astrocyte-laden support bath resembling a neural stem cell niche environment. A photo-crosslinkable bioink and a thermal-healing supporting bath were engineered to mimic the mechanical modulus of soft tissue while supporting the formation of self-organizing neurospheroids within elaborate 3D networks. Moreover, bioprinted neurospheroid-laden structures exhibited the capability to differentiate into neuronal cells. These brain-like co-cultures could provide a reproducible platform for modeling neurological diseases, neural regeneration, and drug development and repurposing.
Assuntos
Bioimpressão , Encéfalo , Técnicas de Cocultura , Hidrogéis , Impressão Tridimensional , Engenharia Tecidual , Alicerces TeciduaisRESUMO
Genome wide association studies (GWAS) in obesity have identified a large number of noncoding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, few obesity-associated SNPs have been functionally characterized. Leptin responsive neurons in the hypothalamus are essential in controlling energy homeostasis and body weight. Here, we combine FACS-sorting of leptin-responsive hypothalamic neuron nuclei with genomic and epigenomic approaches (RNA-seq, ChIP-seq, ATAC-seq) to generate a comprehensive map of leptin-response specific regulatory elements, several of which overlap obesity-associated GWAS variants. We demonstrate the usefulness of our leptin-response neuron regulome, by functionally characterizing a novel enhancer near Socs3, a leptin response-associated transcription factor. We envision our data to serve as a useful resource and a blueprint for functionally characterizing obesity-associated SNPs in the hypothalamus.
Assuntos
Peso Corporal/genética , Epigenômica , Genômica , Leptina/fisiologia , Animais , Estudo de Associação Genômica Ampla , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Camundongos , Neurônios/fisiologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único , TranscriptomaRESUMO
A wide range of human diseases result from haploinsufficiency, where the function of one of the two gene copies is lost. Here, we targeted the remaining functional copy of a haploinsufficient gene using CRISPR-mediated activation (CRISPRa) in Sim1 and Mc4r heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the Sim1 promoter or its distant hypothalamic enhancer up-regulated its expression from the endogenous functional allele in a tissue-specific manner, rescuing the obesity phenotype in Sim1 heterozygous mice. To evaluate the therapeutic potential of CRISPRa, we injected CRISPRa-recombinant adeno-associated virus into the hypothalamus, which led to reversal of the obesity phenotype in Sim1 and Mc4r haploinsufficient mice. Our results suggest that endogenous gene up-regulation could be a potential strategy to treat altered gene dosage diseases.
Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Elementos Facilitadores Genéticos , Haploinsuficiência , Obesidade/genética , Regiões Promotoras Genéticas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular , Dependovirus , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Heterozigoto , Hipotálamo , Mutação com Perda de Função , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/terapia , Fenótipo , Receptor Tipo 4 de Melanocortina/genética , Proteínas Repressoras/genética , Regulação para Cima , Aumento de PesoRESUMO
The spatial organization of metazoan genomes has a direct influence on fundamental nuclear processes that include transcription, replication, and DNA repair. It is imperative to understand the mechanisms that shape the 3D organization of the eukaryotic genomes. Chromatin insulators have emerged as one of the central components of the genome organization tool-kit across species. Recent advancements in chromatin conformation capture technologies have provided important insights into the architectural role of insulators in genomic structuring. Insulators are involved in 3D genome organization at multiple spatial scales and are important for dynamic reorganization of chromatin structure during reprogramming and differentiation. In this review, we will discuss the classical view and our renewed understanding of insulators as global genome organizers. We will also discuss the plasticity of chromatin structure and its re-organization during pluripotency and differentiation and in situations of cellular stress.
RESUMO
Hox clusters have served as a favorite system to study the role of cis-regulatory elements at multiple layers of gene regulation. Organization and regulation of Hox genes show remarkable conservation and determine the anterior-posterior body axis across the bilaterians. Identification of a variety of regulatory regions within the complex and around it, embedded primarily in the noncoding part of the corresponding genomic region that can spread 100-150 kb, is a challenging problem. Multiple experimental and computational tools need to be employed to investigate functional features of such elements. Here we discuss parallel approaches to mine the most plausible regulatory information from the noncoding sequences of Hox clusters, among diverse species.
Assuntos
Biologia Computacional/métodos , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Família Multigênica , Sequências Reguladoras de Ácido Nucleico , Animais , Sequência Conservada , Mineração de Dados , Epigênese Genética , Ordem dos Genes , CamundongosRESUMO
Anterior-posterior body axis in all bilaterians is determined by the Hox gene clusters that are activated in a spatio-temporal order. This expression pattern of Hox genes is established and maintained by regulatory mechanisms that involve higher order chromatin structure and Polycomb group (PcG) and trithorax group (trxG) proteins. We identified earlier a Polycomb response element (PRE) in the mouse HoxD complex that is functionally conserved in flies. We analyzed the molecular and genetic interactions of mouse PRE using Drosophila melanogaster and vertebrate cell culture as the model systems. We demonstrate that the repressive activity of this PRE depends on PcG/trxG genes as well as the heterochromatin components. Our findings indicate that a wide range of factors interact with the HoxD PRE that can contribute to establishing the expression pattern of homeotic genes in the complex early during development and maintain that pattern at subsequent stages.
Assuntos
Heterocromatina/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Elementos de Resposta , Animais , Animais Geneticamente Modificados , Linhagem Celular , Mapeamento Cromossômico , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Epigênese Genética , Expressão Gênica , Ordem dos Genes , Genes Reporter , Genótipo , Heterocromatina/genética , Humanos , Masculino , Camundongos , Complexos Multiproteicos , Mutação , Fenótipo , Ligação Proteica , Temperatura , Fatores de Transcrição/metabolismoRESUMO
Polycomb group (PcG) and trithorax group (trxG) proteins are chromatin-mediated regulators of a number of developmentally important genes including the homeotic genes. In Drosophila melanogaster, one of the trxG members, Trithorax like (Trl), encodes the essential multifunctional DNA binding protein called GAGA factor (GAF). While most of the PcG and trxG genes are conserved from flies to humans, a Trl-GAF homologue has been conspicuously missing in vertebrates. Here, we report the first identification of c-Krox/Th-POK as the vertebrate homologue of GAF on the basis of sequence similarity and comparative structural analysis. The in silico structural analysis of the zinc finger region showed preferential interaction of vertebrate GAF with GAGA sites similar to that of fly GAF. We also show by cross-immunoreactivity studies that both fly and vertebrate GAFs are highly conserved and share a high degree of structural similarity. Electrophoretic mobility shift assays show that vertebrate GAF binds to GAGA sites in vitro. Finally, in vivo studies by chromatin immunoprecipitation confirmed that vertebrate GAF binds to GAGA-rich DNA sequences present in hox clusters. Identification of vertebrate GAF and the presence of its target sites at various developmentally regulated loci, including hox complexes, highlight the evolutionarily conserved components involved in developmental mechanisms across the evolutionary lineage and answer a long-standing question of the presence of vertebrate GAF.
Assuntos
Fatores de Transcrição/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Análise por Conglomerados , Biologia Computacional , Sequência Conservada , Reações Cruzadas , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/imunologia , Ensaio de Desvio de Mobilidade Eletroforética , Modelos Moleculares , Dados de Sequência Molecular , Filogenia , Ligação Proteica , Estrutura Terciária de Proteína , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/imunologia , Proteínas de Peixe-Zebra/imunologia , Dedos de Zinco/genéticaAssuntos
Montagem e Desmontagem da Cromatina/fisiologia , Epigênese Genética/fisiologia , Modelos Biológicos , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Proteínas Repressoras/fisiologia , Saccharomycetales , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/metabolismo , Sirtuína 2/metabolismo , Fatores de TempoRESUMO
There are several observations that are difficult to explain using classical Mendelian inheritance. These include position effect variegation, transvection, telomere position effect and imprinting. These phenomena are now known to be based on changes in chromatin structure and epigenetic modifications that can be transmitted to daughter cells. It is, therefore, possible that abnormal chromatin packaging can lead to abnormal cellular processes that ultimately disturb the cell’s sustenance. For example, de-repression of telomeric heterochromatin can lead to cellular senescence (Kennedy et al. 1997; Moazed 2001). This indicates that during aging the ability to compensate for cellular damage fails to meet the need for repair or replenishment of the maintenance factors (Steinkraus et al. 2008). Non-dividing cells maintain their pool to repair internal damage by optimizing the supply of chromatin components. Actively dividing cells need massive synthesis of such components. Eukaryotic cells cannot undergo cell division indefinitely and, therefore, have an inherent lifespan, called the replicative lifespan. After a certain number of replications, the mother cell accumulates aging-related damage, which ultimately causes it to cease further divisions. In multicellular organisms, each tissue has a characteristic replicative capacity (Cavalier-Smith 1978). Much of the information about aging has come from the yeast Saccharomyces cerevisiae (Steinkraus et al. 2008). Several key factors affecting aging are conserved from yeast to worms to mammals (Kaeberlein et al. 1999; Wood et al. 2004; Kenyon 2010). These include calorie restriction, radical oxygen species (ROS)-dependent signal transduction, sirtuin-mediated anti-aging functions and the target of rapamycin (TOR) pathway. Budding yeasts try to prevent the passing of cellular components with aging-related damage such as damaged proteins, or extra-chromosomal DNA fragments, to the daughter cells during cell division (Kaeberlein et al. 1999). As a cell undergoes many divisions, it becomes increasingly difficult for the cell to prevent passage of this load to the daughter cells. So the accumulation of damaged components can itself act as a trigger for replicative senescence (Steinkraus et al. 2008). Consequently, factors that reduce this load assume the role of safeguarding against the aging process. Many of the factors that prevent aging can alter gene expression via chromatin modifications. Therefore, chromatin modifiers such as Sir2, the Polycomb group (PcG) of proteins (Jacobs et al. 1999), histone deacetylases and histone chaperones (Chen et al. 2008; Dang et al. 2009) are being related to aging processes. Can key structural components of chromatin such as the histone proteins be directly involved in replicative aging? A recent report demonstrates a direct connection between the levels of histones and the lifespan of budding yeast (Feser et al. 2010). It was shown that aging cells have low histone protein levels, resulting in loose packaging of the genome and hence inappropriate gene regulation.