Genes and Development
Công bố khoa học tiêu biểu
Sắp xếp:
Targeting histone deacetylase complexes via KRAB-zinc finger proteins: the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the Mi-2α subunit of NuRD Macromolecular complexes containing histone deacetylase and ATPase activities regulate chromatin dynamics and are vitally responsible for transcriptional gene silencing in eukaryotes. The mechanisms that target these assemblies to specific loci are not as well understood. We show that the corepressor KAP-1, via its PHD (p lanth omeod omain) and bromodomain, links the superfamily of Krüppel associated box (KRAB) zinc finger proteins (ZFP) to the NuRD complex. We demonstrate that the tandem PHD finger and bromodomain of KAP-1, an arrangement often found in cofactor proteins but functionally ill-defined, form a cooperative unit that is required for transcriptional repression. Substitution of highly related PHD fingers or bromodomains failed to restore repression activity, suggesting high specificity in their cooperative function. Moreover, single amino acid substitutions in either the bromodomain or PHD finger, including ones that mimic disease-causing mutations in the hATRX PHD finger, abolish repression. A search for effectors of this repression function yielded a novel isoform of the Mi-2α protein, an integral component of the NuRD complex. Endogenous KAP-1 is associated with Mi-2α and other components of NuRD, and KAP-1-mediated silencing requires association with NuRD and HDAC activity. These data suggest the KRAB-ZFP superfamily of repressors functions to target the histone deacetylase and chromatin remodeling activities of the NuRD complex to specific gene promoters in vivo.
Genes and Development - Tập 15 Số 4 - Trang 428-443 - 2001
Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus
Genes and Development - Tập 17 Số 14 - Trang 1691-1702 - 2003
Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses
Genes and Development - Tập 12 Số 5 - Trang 667-678 - 1998
Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells. Through a proteomics analysis of senescent chromatin, we identified the nuclear factor-κB (NF-κB) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-κB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-κB suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence. In a mouse lymphoma model, NF-κB inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-κB controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-κB that contributes to the outcome of cancer therapy.
Genes and Development - Tập 25 Số 20 - Trang 2125-2136 - 2011
Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging All eukaryotic cells divide a finite number of times, although the mechanistic basis of this replicative aging remains unclear. Replicative aging is accompanied by a reduction in histone protein levels, and this is a cause of aging in budding yeast. Here we show that nucleosome occupancy decreased by 50% across the whole genome during replicative aging using spike-in controlled micrococcal nuclease digestion followed by sequencing. Furthermore, nucleosomes became less well positioned or moved to sequences predicted to better accommodate histone octamers. The loss of histones during aging led to transcriptional induction of all yeast genes. Genes that are normally repressed by promoter nucleosomes were most induced, accompanied by preferential nucleosome loss from their promoters. We also found elevated levels of DNA strand breaks, mitochondrial DNA transfer to the nuclear genome, large-scale chromosomal alterations, translocations, and retrotransposition during aging.
Genes and Development - Tập 28 Số 4 - Trang 396-408 - 2014
Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span Functional data indicate that specific histone modification enzymes can be key to longevity inCaenorhabditis elegans , but the molecular basis of how chromatin structure modulates longevity is not well understood. In this study, we profiled the genome-wide pattern of trimethylation of Lys36 on histone 3 (H3K36me3) in the somatic cells of young and oldCaenorhabditis elegans. We revealed a new role of H3K36me3 in maintaining gene expression stability through aging with important consequences on longevity. We found that genes with dramatic expression change during aging are marked with low or even undetectable levels of H3K36me3 in their gene bodies irrespective of their corresponding mRNA abundance. Interestingly, 3′ untranslated region (UTR) length strongly correlates with H3K36me3 levels and age-dependent mRNA expression stability. A similar negative correlation between H3K36me3 marking and mRNA expression change during aging was also observed inDrosophila melanogaster , suggesting a conserved mechanism for H3K36me3 in suppressing age-dependent mRNA expression change. Importantly, inactivation of the methyltransferasemet-1 resulted in a decrease in global H3K36me3 marks, an increase in mRNA expression change with age, and a shortened life span, suggesting a causative role of the H3K36me3 marking in modulating age-dependent gene expression stability and longevity.
Genes and Development - Tập 29 Số 7 - Trang 718-731 - 2015
Motif module map reveals enforcement of aging by continual NF-κB activity Aging is characterized by specific alterations in gene expression, but their underlying mechanisms and functional consequences are not well understood. Here we develop a systematic approach to identify combinatorial cis -regulatory motifs that drive age-dependent gene expression across different tissues and organisms. Integrated analysis of 365 microarrays spanning nine tissue types predicted fourteen motifs as major regulators of age-dependent gene expression in human and mouse. The motif most strongly associated with aging was that of the transcription factor NF-κB. Inducible genetic blockade of NF-κB for 2 wk in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Age-specific NF-κB blockade and orthogonal cell cycle interventions revealed that NF-κB controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways. These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-κB is continually required to enforce many features of aging in a tissue-specific manner.
Genes and Development - Tập 21 Số 24 - Trang 000.1-000 - 2007
H3K36 methylation promotes longevity by enhancing transcriptional fidelity Epigenetic mechanisms, including histone post-translational modifications, control longevity in diverse organisms. Relatedly, loss of proper transcriptional regulation on a global scale is an emerging phenomenon of shortened life span, but the specific mechanisms linking these observations remain to be uncovered. Here, we describe a life span screen in Saccharomyces cerevisiae that is designed to identify amino acid residues of histones that regulate yeast replicative aging. Our results reveal that lack of sustained histone H3K36 methylation is commensurate with increased cryptic transcription in a subset of genes in old cells and with shorter life span. In contrast, deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes, suppresses cryptic transcript initiation, and extends life span. We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to life span, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity.
Genes and Development - Tập 29 Số 13 - Trang 1362-1376 - 2015
Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators
Genes and Development - Tập 12 Số 24 - Trang 3788-3796 - 1998
Attenuation of the heat shock response in HeLa cells is mediated by the release of bound heat shock transcription factor and is modulated by changes in growth and in heat shock temperatures. When HeLa S3 cells are subjected to a continuous 42 degrees C heat shock, activation of heat shock transcription factor (HSF) and transcriptional activation of the heat shock genes hsp70, hsp89 alpha, and hsp60 is transient, peaking at 40-60 min of heat shock, and then attenuating. We have used in vivo genomic footprinting to demonstrate that attenuation of hsp70 transcription is mediated by release of bound HSF from the heat shock element (HSE) of the hsp70 gene promoter. Release of bound HSF in vivo occurs at a higher rate than would be predicted from in vitro measurements of dissociation. Attenuation of HSF activation and heat shock gene transcription occurs only when mild heat shock temperatures are employed (42 degrees C); increasing the heat shock temperature by 1 degree C elicits a much higher level of activation, which does not attenuate during a 4-hr heat shock. Surprisingly, altering the temperature at which cells are grown prior to heat shock modulates the magnitude and temporal pattern of the response to a given heat shock temperature. This finding suggests that HSF does not sense temperature directly but, instead, may be responsive to the magnitude of the difference between growth and heat shock temperatures.
Genes and Development - Tập 5 Số 11 - Trang 2117-2127 - 1991
Tổng số: 640
- 1
- 2
- 3
- 4
- 5
- 6
- 64