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Distinct RE-1 silencing transcription factor-containing complexes interact with different target genes
Nikolai D Belyaev1, Ian C Wood, Alexander W Bruce
1School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
The Journal of Biological Chemistry
|October 17, 2003
Summary
Neuronal gene regulation involves selective silencing by REST (RE-1 silencing transcription factor). This study reveals distinct mechanisms for REST-mediated repression at the M4 and NaV1.2 genes, challenging unified models of gene silencing.
Area of Science:
- Neuroscience
- Molecular Biology
- Epigenetics
Background:
- Neuronal identity relies on coordinated gene expression, with neuron-specific genes activated in neurons and repressed in non-neuronal cells.
- The RE-1 silencing transcription factor (REST) is implicated in repressing neuron-specific genes in non-neuronal cells via histone deacetylase (HDAC) complexes.
- However, REST's in vivo role as an obligate silencer is limited to a subset of its target genes, indicating context-dependent mechanisms.
Purpose of the Study:
- To investigate the interaction of REST and its associated co-repressors (Co-REST, Sin3A, HDAC1, HDAC2) with two key endogenous neuronal target genes: the M4 muscarinic receptor and the sodium type II channel (NaV1.2).
- To elucidate the distinct mechanisms of transcriptional repression employed at these specific loci.
Main Methods:
- Analysis of REST, Co-REST, Sin3A, HDAC1, and HDAC2 interactions with the M4 and NaV1.2 genes.
- Chromatin domain analysis to assess gene localization.
- Investigation of epigenetic markers of gene silencing, including DNA methylation and histone modifications (H3K9 dimethylation).
- Assessment of heterochromatin protein 1 (HP1) co-localization.
Main Results:
- The NaV1.2 gene is actively transcribed but repressed by REST independently of histone deacetylation or DNA methylation, without co-localizing with canonical silencing markers like H3K9 dimethylation and HP1.
- The M4 gene is maintained in a silent state independently of REST, co-localizing with H3K9 dimethylation and HP1alpha/gamma, indicative of silenced euchromatin.
- These findings contrast with previous reports of coordinate REST-dependent regulation at the M4 locus.
Conclusions:
- Distinct repressor complexes and silencing mechanisms operate at different loci, even within cell lines of common embryological origin.
- REST-mediated repression is not universally dependent on HDAC recruitment or canonical heterochromatin formation.
- The regulation of neuronal gene expression is more complex and locus-specific than previously assumed.