Biomedical subjects

Stavros Lomvardas

Publications and source records attributed to Stavros Lomvardas.

5 recordsLinked to original sources

PubMed2006

Interchromosomal interactions and olfactory receptor choice.

The expression of a single odorant receptor (OR) gene from a large gene family in individual sensory neurons is an essential feature of the organization and function of the olfactory system. We have used chromosome conformation capture to demonstrate the specific association of an enhancer element, H, on chromosome 14 with multiple OR gene promoters on different chromosomes. DNA and RNA fluorescence in situ hybridization (FISH) experiments allow us to visualize the colocalization of the H enhancer with the single OR allele that is transcribed in a sensory neuron. In transgenic mice bearing additional H elements, sensory neurons that express OR pseudogenes also express a second functional receptor. These data suggest a model of receptor choice in which a single trans-acting enhancer element may allow the stochastic activation of only one OR allele in an olfactory sensory neuron.

Alleles↗

PubMed2003

p38 MAP kinase mediates both short-term and long-term synaptic depression in aplysia.

At Aplysia sensory-to-motor neuron synapses, the inhibitory neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFa) produces depression, and serotonin (5-HT) produces facilitation. Short-term depression has been found to result from the activation of a phospholipase A2. The released arachidonate is metabolized by 12-lipoxygenase to active second messengers. We find that FMRFa leads to the phosphorylation and activation of p38 mitogen-activated protein (MAP) kinase. Short-term depression and the release of arachidonate are blocked by the specific p38 kinase inhibitor SB 203580. Both the inhibitor and an affinity-purified antibody raised against recombinant Aplysia p38 kinase injected into sensory neurons prevented long-term depression, which depends on the phosphorylation of translation factors cAMP response element-binding protein 2 (CREB2) and activating transcription factor 2. Facilitation produced by 5-HT, on the other hand, inactivates p38 kinase. Chromatin immunoprecipitation assays indicate that p38 kinase activates CREB2. p38 kinase also is pivotal in the bidirectional regulation of synaptic plasticity: when the kinase is inhibited, brief treatment with 5-HT that normally produces only short-term facilitation now results in long-term facilitation. Conversely, in sensory neurons injected with the activated kinase, long-term facilitation is blocked, and brief exposure to FMRFa, which normally results in short-term depression, results in long-term depression. We conclude that p38 kinase, which itself is bidirectionally regulated by FMRFa and 5-HT, acts as a modulator of synaptic plasticity by positively regulating depression and serving as an inhibitory constraint for facilitation.

Activating Transcription Factor 2↗

PubMed2002

Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure.

Excitatory and inhibitory inputs converge on single neurons and are integrated into a coherent output. Although much is known about short-term integration, little is known about how neurons sum opposing signals for long-term synaptic plasticity and memory storage. In Aplysia, we find that when a sensory neuron simultaneously receives inputs from the facilitatory transmitter 5-HT at one set of synapses and the inhibitory transmitter FMRFamide at another, long-term facilitation is blocked and synapse-specific long-term depression dominates. Chromatin immunoprecipitation assays show that 5-HT induces the downstream gene C/EBP by activating CREB1, which recruits CBP for histone acetylation, whereas FMRFa leads to CREB1 displacement by CREB2 and recruitment of HDAC5 to deacetylate histones. When the two transmitters are applied together, facilitation is blocked because CREB2 and HDAC5 displace CREB1-CBP, thereby deacetylating histones.

Acetylation↗

PubMed2002

Modifying gene expression programs by altering core promoter chromatin architecture.

Transcriptional activation of the IFN-beta gene in response to virus infection requires the assembly of an enhanceosome, which instructs a recruitment program of chromatin modifiers/remodelers and general transcription factors to the promoter. This program culminates with sliding of a nucleosome blocking the core promoter to a downstream position, a prerequisite for transcriptional activation. We show that delivery of this nucleosome to the same downstream position to create an accessible IFN-beta core promoter prior to enhanceosome assembly results in major changes in the gene expression program with regard to the temporal pattern and the signal specificity of the transcriptional response. Thus, the identity of a gene expression program is achieved and maintained by the dynamic interplay between specific enhanceosomes and specific local chromatin structure.

Chromatin↗

PubMed2002

Opening chromatin.

How the transcriptional apparatus gains access to and subsequently opens compacted chromatin has remained a mystery. Now in this issue of Molecular Cell, Zaret and coworkers show that chromatin opening in vitro is not mediated by the classical chromatin remodeling machines but instead occurs through specific transcription factor-histone interactions.

Animals↗