Comparative genomics modeling of the NRSF/REST repressor network: From single conserved sites to genome-wide repertoire

Mortazavi, A; Thompson, Evonne Chen Leeper; Garcia, Sarah; Myers, R; Wold, B

doi:10.1101/gr.4997306

Cited by 152 publications

(169 citation statements)

References 53 publications

Supporting

Mentioning

159

Contrasting

Order By: Relevance

“…Bioinformatics analysis predicts nearly 2,000 REST target genes within the mammalian genomes (51) and in immortalized Jurkat cells (31). What then determines the specificity of interaction between REST and target genes?…”

Section: Discussionmentioning

confidence: 99%

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

Noh¹,

Hwang²,

Follenzi³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

165

180

View full text Add to dashboard Cite

Dysregulation of the transcriptional repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor is important in a broad range of diseases, including cancer, diabetes, and heart disease. The role of REST-dependent epigenetic modifications in neurodegeneration is less clear. Here, we show that neuronal insults trigger activation of REST and CoREST in a clinically relevant model of ischemic stroke and that REST binds a subset of "transcriptionally responsive" genes (gria2, grin1, chrnb2, nefh, nfκb2, trpv1, chrm4, and syt6), of which the AMPA receptor subunit GluA2 is a top hit. Genes with enriched REST exhibited decreased mRNA and protein. We further show that REST assembles with CoREST, mSin3A, histone deacetylases 1 and 2, histone methyl-transferase G9a, and methyl CpG binding protein 2 at the promoters of target genes, where it orchestrates epigenetic remodeling and gene silencing. RNAi-mediated depletion of REST or administration of dominant-negative REST delivered directly into the hippocampus in vivo prevents epigenetic modifications, restores gene expression, and rescues hippocampal neurons. These findings document a causal role for REST-dependent epigenetic remodeling in the neurodegeneration associated with ischemic stroke and identify unique therapeutic targets for the amelioration of hippocampal injury and cognitive deficits.chromatin remodeling | global ischemia | CA1 | synaptic plasticity

show abstract

Section: Discussionmentioning

confidence: 99%

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

Noh¹,

Hwang²,

Follenzi³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

165

180

View full text Add to dashboard Cite

show abstract

“…Plasmids-Plasmids for in vitro transcription/translation and/or mammalian expression of REST, MED1, 6,7,8,9,10,11,12,14,15,18,19,20,21,22,23,24,25,26,27,28,29, and CDK8L have been described (37)(38)(39)(40)(41)(42)(43)(44)(45). pCS3ϩCDK8-FLAG, pCS3ϩCycC-FLAG, pCS3ϩMED31-FLAG, pCS3ϩMED16-FLAG, and pCS3ϩMED17-FLAG were constructed by subcloning PCR-amplified corresponding cDNAs into XhoI/ClaIlinearized pCS3ϩ vectors bearing FLAG epitope tag sequence.…”

Section: Methodsmentioning

confidence: 99%

MED19 and MED26 Are Synergistic Functional Targets of the RE1 Silencing Transcription Factor in Epigenetic Silencing of Neuronal Gene Expression

Ding

Tomomori-Sato

Sato

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

A key hub for the orchestration of epigenetic modifications necessary to restrict neuronal gene expression to the nervous system is the RE1 silencing transcription factor (REST; also known as neuron restrictive silencer factor, NRSF). REST suppresses the nonspecific and premature expression of neuronal genes in non-neuronal and neural progenitor cells, respectively, via recruitment of enzymatically diverse corepressors, including G9a histone methyltransferase (HMTase) that catalyzes di-methylation of histone 3-lysine 9 (H3K9me2). Recently, we identified the RNA polymerase II transcriptional Mediator to be an essential link between RE1-bound REST and G9a in epigenetic suppression of neuronal genes in non-neuronal cells. However, the means by which REST recruits Mediator to facilitate G9a-dependent extra-neuronal gene silencing remains to be elucidated. Here, we identify the MED19 and MED26 subunits in Mediator as direct physical and synergistic functional targets of REST. We show that although REST independently binds to both MED19 and MED26 in isolation, combined depletion of both subunits is required to disrupt the association of REST with Mediator. Furthermore, combined, but not individual, depletion of MED19/MED26 impairs REST-directed recruitment to RE1 elements of Mediator and G9a, leading to a reversal of G9a-dependent H3K9me2 and de-repression of REST-target gene expression. Together, these findings identify MED19/ MED26 as a probable composite REST interface in Mediator and further clarify the mechanistic basis by which Mediator facilitates REST-imposed epigenetic restrictions on neuronal gene expression.

show abstract

“…Progress in addressing this question has been hampered by the lack of a well defined consensus REST DNA sequence motif, which is unusually large, and a reliable methodology for interrogating functional binding in vivo. A recent in silico study of REST-binding sites, however, has estimated that only 11% of neuronal-specific genes contained a REST-binding site, suggesting that the types of genes regulated by REST might represent a relatively small subset of the neuronal gene repertoire (Mortazavi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

A New Binding Motif for the Transcriptional Repressor REST Uncovers Large Gene Networks Devoted to Neuronal Functions

Otto¹,

McCorkle²,

Hover³

et al. 2007

Journal of Neuroscience

213

262

View full text Add to dashboard Cite

The repressor element 1 (RE1) silencing transcription factor (REST) helps preserve the identity of nervous tissue by silencing neuronal genes in non-neural tissues. Moreover, in an epithelial model of tumorigenesis, loss of REST function is associated with loss of adhesion, suggesting the aberrant expression of REST-controlled genes encoding this property. To date, no adhesion molecules under REST control have been identified. Here, we used serial analysis of chromatin occupancy to perform genome-wide identification of REST-occupied target sequences (RE1 sites) in a kidney cell line. We discovered novel REST-binding motifs and found that the number of RE1 sites far exceeded previous estimates. A large family of targets encoding adhesion proteins was identified, as were genes encoding signature proteins of neuroendocrine tumors. Unexpectedly, genes considered exclusively non-neuronal also contained an RE1 motif and were expressed in neurons. This supports the model that REST binding is a critical determinant of neuronal phenotype.

show abstract

Comparative genomics modeling of the NRSF/REST repressor network: From single conserved sites to genome-wide repertoire

Cited by 152 publications

References 53 publications

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

MED19 and MED26 Are Synergistic Functional Targets of the RE1 Silencing Transcription Factor in Epigenetic Silencing of Neuronal Gene Expression

A New Binding Motif for the Transcriptional Repressor REST Uncovers Large Gene Networks Devoted to Neuronal Functions

Contact Info

Product

Resources

About