Project description:DREAM complex is known to regulate DNA repair and cell cycle-regulated genes in a p53-p21 dependent axis. This experiment identified an alternate pathway of DREAM target regulation.
Project description:DREAM complex is known to regulate DNA repair and cell cycle-regulated genes in a p53-p21 dependent axis. This experiment identified an alternate pathway of DREAM target regulation.
Project description:The master transcriptional repressor DREAM (dimerization partner, RB-like, E2F and multi-vulval class B) complex regulates cell cycle in eukaryotes, but much remains unknown about how it transmits repressive signals on chromatin to the primary transcriptional machinery (e.g., Pol II). Through a genetic screen, we identified BTE1 (barrier of transcription elongation 1), a key component in the plant DREAM complex. The subsequent characterization demonstrated that the DREAM complex represses Pol II elongation. The core DREAM subunits E2F transcription factors recruit BTE1 to accumulate at the promoter-proximal regions of target genes. DREAM target genes exhibit characteristic enrichment of H2A.Z and H3K4me2 modification on chromatin. The DREAM complex BTE1 subunit interacts with WDR5a, repressing WDR5a chromatin binding and the productive elongation of transcription on BTE1-targeted genomic loci. Thus, we demonstrate a major role of DREAM complex in the control of transition from transcription initiation to productive elongation around TSSs on the open chromatin via inhibiting WDR5a function.
Project description:The DREAM (DP, Retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell cycle and other genes, but its mechanism of action is unclear. Here we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z. Furthermore, the function of DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses a subset of germline targets by facilitating H3K9me2 promoter marking. In humans, THAP proteins have been implicated in cell cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function, facilitating repression of distinct sets of targets.
Project description:Mutations in the DREAM complex induce germline-like gene expression patterns including the increase of multiple mechanisms of DNA repair in the soma of Caenorhabditis elegans. This confers mutants of the DREAM complex resistance to a wide range of DNA damage types during development and aging.
Project description:DREAM (downstream regulatory element antagonist modulator) is a Ca2+-binding protein that binds DNA and represses transcription in a Ca2+-dependent manner. Previous studies have shown a role for DREAM in cerebellar function regulating the expression of the sodium/calcium exchanger3 (NCX3) in cerebellar granules to control Ca2+ homeostasis and survival of these neurons. To achieve a more global view of the genes regulated by DREAM in the cerebellum, we performed a genome-wide analysis in transgenic cerebellum expressing a Ca2+-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Our results indicate that DREAM is a major transcription factor in the cerebellum that regulates genes important for cerebellar development. We used Affymetrix microarrays (GeneChip Mouse Genome 430 2.0) to compare global gene expression in wild type (WT) versus transgenic cerebellum cells. For ech type of sample three hybridizations were carried-out (independent biological replicates).
Project description:The master transcriptional repressor DREAM (dimerization partner, RB-like, E2F and multi-vulval class B) complex regulates cell cycle in eukaryotes, but much remains unknown about how it transmits repressive signals on chromatin to the primary transcriptional machinery (e.g., Pol II). Through a genetic screen, we identified BTE1 (barrier of transcription elongation 1), a key component in the plant DREAM complex. The subsequent characterization demonstrated that the DREAM complex represses Pol II elongation. The core DREAM subunits E2F transcription factors recruit BTE1 to accumulate at the promoter-proximal regions of target genes. DREAM target genes exhibit characteristic enrichment of H2A.Z and H3K4me2 modification on chromatin. The DREAM complex BTE1 subunit interacts with WDR5a, repressing WDR5a chromatin binding and the productive elongation of transcription on BTE1-targeted genomic loci. Thus, we demonstrate a major role of DREAM complex in the control of transition from transcription initiation to productive elongation around TSSs on the open chromatin via inhibiting WDR5a function.
Project description:The master transcriptional repressor DREAM (dimerization partner, RB-like, E2F and multi-vulval class B) complex regulates cell cycle in eukaryotes, but much remains unknown about how it transmits repressive signals on chromatin to the primary transcriptional machinery (e.g., Pol II). Through a genetic screen, we identified BTE1 (barrier of transcription elongation 1), a key component in the plant DREAM complex. The subsequent characterization demonstrated that the DREAM complex represses Pol II elongation. The core DREAM subunits E2F transcription factors recruit BTE1 to accumulate at the promoter-proximal regions of target genes. DREAM target genes exhibit characteristic enrichment of H2A.Z and H3K4me2 modification on chromatin. The DREAM complex BTE1 subunit interacts with WDR5a, repressing WDR5a chromatin binding and the productive elongation of transcription on BTE1-targeted genomic loci. Thus, we demonstrate a major role of DREAM complex in the control of transition from transcription initiation to productive elongation around TSSs on the open chromatin via inhibiting WDR5a function.
Project description:DREAM (downstream regulatory element antagonist modulator) is a Ca2+-binding protein that binds DNA and represses transcription in a Ca2+-dependent manner. Previous studies have shown a role for DREAM in cerebellar function regulating the expression of the sodium/calcium exchanger3 (NCX3) in cerebellar granules to control Ca2+ homeostasis and survival of these neurons. To achieve a more global view of the genes regulated by DREAM in the cerebellum, we performed a genome-wide analysis in transgenic cerebellum expressing a Ca2+-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Our results indicate that DREAM is a major transcription factor in the cerebellum that regulates genes important for cerebellar development.
Project description:Deregulated intracellular Ca2+ homeostasis underlies synaptic dysfunction and is a common feature in neurodegenerative processes, including Huntington's disease (HD). DREAM/calsenilin/KChIP-3 is a multifunctional Ca2+ binding protein that controls the expression level and/or the activity of several proteins related to Ca2+ homeostasis, neuronal excitability and neuronal survival. We found that expression of endogenous DREAM (DRE antagonist modulator) is reduced in the striatum of R6 mice, in STHdh-Q111/111 knock in striatal neurons and in HD patients. DREAM down regulation in R6 striatum occurs early after birth, well before the onset of motor coordination impairment, and could be part of an endogenous mechanism of neuroprotection, since i) R6/2 mice hemizygous for the DREAM gene (R6/2xDREAM+/-) showed delayed onset of locomotor impairment and prolonged lifespan, ii) motor impairment after chronic administration of 3-NPA was reduced in DREAM knockout mice and enhanced in daDREAM transgenic mice and, iii) lentiviral-mediated DREAM expression in STHdh-Q111/111 knock in cells sensitizes them to oxidative stress. Transcriptomic analysis showed that changes in gene expression in R6/2 striatum were notably reduced in R6/2xDREAM+/- striatum. Chronic administration of repaglinide, a molecule able to bind to DREAM in vitro and to accelerate its clearance in vivo, delayed the onset of motor dysfunction, reduced striatal loss and prolonged the lifespan in R6/2 mice. Furthermore, exposure to repaglinide protected STHdh-Q111/111 knock in striatal neurons sensitized to oxidative stress by lentiviral-mediated DREAM overexpression. Thus, genetic and pharmacological evidences disclose a role for DREAM silencing in early neuroprotective mechanisms in HD.