RESUMO
Sophisticated gene-regulatory mechanisms probably evolved in prokaryotes billions of years before the emergence of modern eukaryotes, which inherited the same basic enzymatic machineries. However, the epigenomic landscapes of eukaryotes are dominated by nucleosomes, which have acquired roles in genome packaging, mitotic condensation and silencing parasitic genomic elements. Although the molecular mechanisms by which nucleosomes are displaced and modified have been described, just how transcription factors, histone variants and modifications and chromatin regulators act on nucleosomes to regulate transcription is the subject of considerable ongoing study. We explore the extent to which these transcriptional regulatory components function in the context of the evolutionarily ancient role of chromatin as a barrier to processes acting on DNA and how chromatin proteins have diversified to carry out evolutionarily recent functions that accompanied the emergence of differentiation and development in multicellular eukaryotes.
Assuntos
Montagem e Desmontagem da Cromatina , DNA/genética , Genoma , Nucleossomos/genética , Transcrição Gênica , Animais , Evolução Biológica , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/história , Proteínas Cromossômicas não Histona/metabolismo , DNA/história , DNA/metabolismo , Células Eucarióticas/citologia , Células Eucarióticas/metabolismo , Genômica/métodos , Histonas/genética , Histonas/história , Histonas/metabolismo , História do Século XXI , História Antiga , Humanos , Nucleossomos/química , Nucleossomos/metabolismo , Células Procarióticas/citologia , Células Procarióticas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/história , Fatores de Transcrição/metabolismoRESUMO
This year's Albert Lasker Basic Medical Research Award honors David Allis and Michael Grunstein for their pioneering research that highlighted the importance of histones and their post-translational modifications in the direct control of gene expression.
Assuntos
Cromatina/fisiologia , Histonas/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Distinções e Prêmios , Pesquisa Biomédica , Expressão Gênica , Código das Histonas , Histonas/história , História do Século XXI , HumanosRESUMO
Together with David Allis, Michael Grunstein just received the Lasker Basic Medical research award. The article that follows is a transcript of a conversation with Jacques Deguine, scientific editor at Cell, that was edited for length. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.
Assuntos
Histonas/metabolismo , Histonas/fisiologia , Animais , Distinções e Prêmios , Biologia , Histonas/história , História do Século XXI , Pesquisa , Ouriços-do-MarRESUMO
Epigenetics now refers to the study or research field related to DNA methylation and histone modifications. Historically, global DNA hypomethylation was first revealed in 1983, and, after a decade, silencing of a tumor suppressor gene by regional DNA hypermethylation was reported. After the proposal of the histone code in the 2000s, alterations of histone methylation were also identified in cancers. Now, it is established that aberrant epigenetic alterations are involved in cancer development and progression, along with mutations and chromosomal losses. Recent cancer genome analyses have revealed a large number of mutations of epigenetic modifiers, supporting their important roles in cancer pathogenesis. Taking advantage of the reversibility of epigenetic alterations, drugs targeting epigenetic regulators and readers have been developed for restoration of normal pattern of the epigenome, and some have already demonstrated clinical benefits. In addition, DNA methylation of specific marker genes can be used as a biomarker for cancer diagnosis, including risk diagnosis, detection of cancers, and pathophysiological diagnosis. In this paper, we will summarize the major concepts of cancer epigenetics, placing emphasis on history.
Assuntos
Metilação de DNA , Epigenômica/história , Histonas/história , Neoplasias/história , Antineoplásicos/história , Antineoplásicos/uso terapêutico , Ilhas de CpG , Epigênese Genética/efeitos dos fármacos , Glioma/genética , Glioma/história , Histonas/genética , Histonas/metabolismo , História do Século XX , História do Século XXI , Mutação , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
The study of histone acetylation in plants started with protein purification and sequencing, with gel analysis and the use of radioactive tracers. In alfalfa, acid urea Triton gel electrophoresis and in vivo labeling with tritated acetate and lysine quantified dynamic acetylation of core histones and identified the replication-coupled and -independent expression patterns of the histone H3.1 and H3.2 variants. Pulse-chase analyses demonstrated protein turnover of newly synthesized histone H3.2 and thereby identified the replacement H3 histones of plants which maintain the nucleosome density of transcribed chromatin. Sequence analysis of histone H4 revealed acetylation of lysine 20, a site typically methylated in animals and yeasts. Histone deacetylase inhibitors butyrate and trichostatin A are metabolized in alfalfa, but loss of TSA is slow, allowing its use to induce transient hyperacetylation of histones H2B, H4 and H3. This article is part of a Special Issue entitled: Epigenetic Control of cellular and developmental processes in plants.
Assuntos
Histonas/história , Plantas/genética , Plantas/metabolismo , Acetilação , Sequência de Aminoácidos , Sequência Conservada , Epigênese Genética , Histonas/genética , Histonas/metabolismo , História do Século XX , Medicago sativa/genética , Medicago sativa/metabolismo , Dados de Sequência Molecular , Processamento de Proteína Pós-Traducional , Pesquisa/história , Homologia de Sequência de AminoácidosAssuntos
Bioquímica/história , Animais , Cromatina/genética , Cromatina/metabolismo , Histona Acetiltransferases/história , Histona Acetiltransferases/metabolismo , Histonas/história , Histonas/metabolismo , História do Século XX , História do Século XXI , Tetrahymena/enzimologia , Tetrahymena/genética , Estados UnidosRESUMO
Two phenomena have long been observed to correlate with transcriptionally active chromatin: increased histone acetylation and increased sensitivity to nucleases, including specific patterns of nuclease hypersensitivity in the promoters of active or inducible genes. Work in recent years has at last identified protein complexes required to form these hallmarks of active chromatin: histone acetyltransferases (HATs) and ATP-dependent chromatin remodeling complexes. This review traces the history of these discoveries, including the development of essential tools that allowed the major advances in the field, and describes the current understanding of the interactions between HATs and ATP-dependent remodelers.
