Biomedical subjects

Nikolai D Belyaev

Publications and source records attributed to Nikolai D Belyaev.

7 recordsLinked to original sources

PubMed2006

BRG1 chromatin remodeling activity is required for efficient chromatin binding by repressor element 1-silencing transcription factor (REST) and facilitates REST-mediated repression.

Chromatin remodeling enzymes such as SWI/SNF use the hydrolysis of ATP to power the movement of nucleosomes with respect to DNA. BRG1, one of the ATPases of the SWI/SNF complex, can be recruited by both activators and repressors, although the precise role of BRG1 in mechanisms of repression has thus far remained unclear. One transcription factor that recruits BRG1 as a corepressor is the repressor element 1-silencing transcription factor (REST). Here we address for the first time the mechanism of BRG1 activity in gene repression. We found that BRG1 enhanced REST-mediated repression at some REST target genes by increasing the interaction of REST with the local chromatin at its binding sites. Furthermore, REST-chromatin interactions, mediated by BRG1, were enhanced following an increase in histone acetylation in a manner dependent on the BRG1 bromodomain. Our data suggest that BRG1 facilitates REST repression by increasing the interaction between REST and chromatin. Such a mechanism may be applicable to other transcriptional repressors that utilize BRG1.

Acetylation↗

PubMed2005

Distinct profiles of REST interactions with its target genes at different stages of neuronal development.

Differentiation of pluripotent embryonic stem (ES) cells through multipotent neural stem (NS) cells into differentiated neurons is accompanied by wholesale changes in transcriptional programs. One factor that is present at all three stages and a key to neuronal differentiation is the RE1-silencing transcription factor (REST/NRSF). Here, we have used a novel chromatin immunoprecipitation-based cloning strategy (SACHI) to identify 89 REST target genes in ES cells, embryonic hippocampal NS cells and mature hippocampus. The gene products are involved in all aspects of neuronal function, especially neuronal differentiation, axonal growth, vesicular transport and release, and ionic conductance. Most target genes are silent or expressed at low levels in ES and NS cells, but are expressed at much higher levels in hippocampus. These data indicate that the REST regulon is specific to each developmental stage and support the notion that REST plays distinct roles in regulating gene expression in pluripotent ES cells, multipotent NS cells, and mature neurons.

Animals↗

PubMed2003

Interaction of the repressor element 1-silencing transcription factor (REST) with target genes.

The repressor element 1-silencing transcription factor (REST) has been proposed to restrict expression of repressor element 1 (RE1) bearing genes to differentiated neurons by silencing their expression in non-neural tissue. Here, we have examined the interaction of REST with the M(4) muscarinic acetylcholine receptor gene. We show that REST binds to the RE1 of the M(4) gene in those cell lines and brain regions where the M(4) gene is expressed but not in those where the M(4) is not expressed. Furthermore, in cells that express M(4), the presence of REST represses but is insufficient to silence transcription of M(4). In non-neural cells REST is absent from the RE1 of the silent M(4) gene and perturbation of REST function fails to induce M(4) expression. We propose that REST acts to regulate expression levels of some RE1-bearing genes in neural cells, thereby playing an important role in defining neuronal activity.

Base Sequence↗

PubMed2003

Distinct RE-1 silencing transcription factor-containing complexes interact with different target genes.

Establishment of neuronal identity requires co-ordinated expression of specific batteries of genes. These programs of gene expression are executed by activation of neuron-specific genes in neuronal cells and their repression in non-neuronal cells. Such co-ordinate regulation requires that individual activators and repressors regulate transcription from specific subsets of their potential target genes, yet we know little of the mechanisms that underlie this selective process. The RE-1 silencing transcription factor (REST) is a repressor that is proposed to silence transcription of numerous neuron-specific genes in non-neuronal cells via recruitment of two independent histone deacetylase (HDAC)-containing co-repressor complexes. However, in vivo, REST appears to be an obligate silencer for only a minority of RE-1-bearing genes. Here we examine the interaction of REST, Co-REST, Sin3A, HDAC1, and HDAC2 with two archetypical endogenous target genes, the M4 muscarinic receptor and the sodium type II channel (NaV1.2) genes. We find that these genes are present in distinct chromosomal domains. The NaV1.2 gene is actively transcribed but repressed by REST independently of histone deacetylation or DNA methylation and does not co-localize with epigenetic markers of silence, including dimethylation of H3K9 and HP1. In contrast, the M4 gene is maintained in a silent state independently of REST and co-localizes with dimethylated H3K9 and HP1alpha and HP1gamma, characteristic of silenced or senescent euchromatic DNA. This contrasts with the coordinate REST-dependent regulation of this locus reported previously. Taken together, we infer that distinct repressor complexes and mechanisms are operative at particular loci even in cell lines derived from a common embryological origin.

Animals↗

PubMed2003

Centromere-specific acetylation of histone H4 in barley detected through three-dimensional microscopy.

Histone acetylation affects chromatin conformation and transcriptional activity. However, the structural role of histone acetylation at specific chromosomal regions, such as the centromere, is poorly understood. In this study, histone H4 acetylation and its localization in barley interphase nuclei are revealed by three-dimensional microscopy. The centromeres form a ring-like allocation near the nuclear membrane in barley. Immunofluorescence studies on non-fixed, interphase nuclei treatment revealed ring-like distribution of the highly acetylated histone H4, located near the nuclear membrane at one pole of the nucleus. This fluorescent structure was similar to the centromere cluster and referred to as hyperacetylated region (HAR). The distribution pattern of the acetylated histone H4 was similar to each of the K5, K8, K12 and K16 lysine residues, although H4 acetylated at K5, K8 and K12 residues was found in almost all nuclei, whereas H4 acetylated at K16 was weakly observed in only half of the nuclei. Each HAR consists of two strongly acetylated cores and a halo-like, less acetylated surrounding area. Fluorescence signals from centromere-specific repetitive sequences of barley, detected through three-dimensional fluorescence in situ hybridization (3D-FISH), co-localized with the HAR corresponding to the K5 residue acetylation, but the signals did not completely overlap each other. These findings indicate that histone acetylation specifically occurring at the centromeres likely have certain structural roles for the centromere.

Acetylation↗

PubMed2003

Association between the cholesteryl ester transfer protein TaqI-detectable B polymorphism and low high-density lipoprotein cholesterol concentration in Saudis.

Plasma concentrations of HDL (high-density lipoprotein) cholesterol are low in the Saudi Arabian population. A B polymorphism at the CETP (cholesteryl ester protein transfer) locus that is detectable with the restriction enzyme Taq I is a genetic determinant of the plasma HDL cholesterol concentration. We assessed the relationship between the Taq I B CETP polymorphism and lipid and apolipoprotein concentrations in a study sample of 335 Saudi residents. The Taq I B1 and B2 allele frequencies were 0.54 and 0.46 respectively, similar to those in other populations. HDL cholesterol levels in B2B2 homozygotes were significantly higher than in B1B1 homozygotes [1.01 (0.3) compared with 0.92 (0.2) mmol/l; mean (S.D.); P=0.03]. There was also a significant difference between the B2B2 and B1B1 homozygotes with regard to apolipoprotein AI concentration [123.6 (16.4) compared with 113.7 (13.9) mg/dl; P=0.04]. This genetic variation was independent of metabolic risk factors known to influence HDL cholesterol levels. The allele frequency of the Taq I B CETP polymorphism and its relatively modest impact on HDL cholesterol concentrations argue against an important role for this allele, or for strongly linked loci, in determining the low levels of HDL cholesterol seen in the Saudi population.

Adult↗

PubMed2002

Cell cycle-dependent and lysine residue-specific dynamic changes of histone H4 acetylation in barley.

Histone acetylation affects chromatin conformation and regulates various cellular functions, such as transcription and cell cycle progression. Although mitosis dependent transcriptional silencing and large-scale chromatin structural changes are well established, acetylation of histone H4 during the mitosis is poorly understood in plants. Here, the dynamics of acetylation of histone H4 in defined genome regions has been examined in the fixed barley cells throughout the mitosis by three-dimensional microscopy. Patterns of strong acetylation of the two lysine residues K5 and K16 of histone H4 in the barley genomes were found to be different. In interphase nuclei, H4 acetylated at K 16 was associated with the gene-rich, telomere-associated hemispheres, whereas K5 acetylation was detected in centromeric regions where the heterochromatin is distributed. Regions of strong K5 acetylation changed dynamically as the cell cycle proceeded. At prometaphase, centromeric acetylation at K5 decreased suddenly, with accompanying rapid increases of acetylation in the nucleolar organizing regions (NORs). Reverse changes occurred at telophase. On the other hand, the strongly acetylated regions of the K16 showed changes compatible with transcriptional activities and chromosome condensation throughout the cell cycle. Telomeric acetylation at K16 was detected throughout the cell cycle, although it was reduced at metaphase which corresponds to the most condensed stage of the chromosomes. It is concluded that dynamic changes in H4 acetylation occur in a lysine residue-, stage-, and region-specific manner and that they correlate with changes in the chromosome structure through the cell cycle.

Acetylation↗