Polycomb Group Proteins as Epigenetic Mediators of Neuroprotection in Ischemic Tolerance

Stapels, Martha; Piper, Chelsea; Yang, Tao; Li, Minghua; Stowell, Cheri; Xiong, Zhi‐Gang; Saugstad, Julie A.; Simon, Roger P.; Geromanos, Scott; Langridge, James; Lan, Jing-Quan; Zhou, An

doi:10.1126/scisignal.2000502

Cited by 93 publications

(105 citation statements)

References 40 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…Recent studies indicate that polycomb repressive complex 2 (PRC2) is recruited to RE1-containing genes by REST via the noncoding RNA HOTAIR (54) and that PRC1 interacts with REST at RE1 sites (55). Moreover, polycomb proteins are activated and afford neuroprotection in the setting of ischemic preconditioning (56).…”

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.

163

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.

163

180

View full text Add to dashboard Cite

show abstract

“…Differential demethylation and expression of Phc2 in injury may also be important. Several members of the polycomb family have been shown recently to be differentially upregulated and essential for the establishment of ischemic tolerance (Stapels et al, 2010). These included the polycomb repressive complex 1 (PRC1) member BMI1, which protects against chemical stress-induced cell death (Lee et al, 2008) and with which Phc2 has been shown to interact (Satijn et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Differential DNA Methylation Patterns Define Status Epilepticus and Epileptic Tolerance

Miller-Delaney¹,

Das²,

Sano³

et al. 2012

J. Neurosci.

View full text Add to dashboard Cite

Prolonged seizures (status epilepticus) produce pathophysiological changes in the hippocampus that are associated with large-scale, wide-ranging changes in gene expression. Epileptic tolerance is an endogenous program of cell protection that can be activated in the brain by previous exposure to a non-harmful seizure episode before status epilepticus. A major transcriptional feature of tolerance is gene downregulation. Here, through methylation analysis of 34,143 discrete loci representing all annotated CpG islands and promoter regions in the mouse genome, we report the genome-wide DNA methylation changes in the hippocampus after status epilepticus and epileptic tolerance in adult mice. A total of 321 genes showed altered DNA methylation after status epilepticus alone or status epilepticus that followed seizure preconditioning, with Ͼ90% of the promoters of these genes undergoing hypomethylation. These profiles included genes not previously associated with epilepsy, such as the polycomb gene Phc2. Differential methylation events generally occurred throughout the genome without bias for a particular chromosomal region, with the exception of a small region of chromosome 4, which was significantly overrepresented with genes hypomethylated after status epilepticus. Surprisingly, only few genes displayed differential hypermethylation in epileptic tolerance. Nevertheless, gene ontology analysis emphasized the majority of differential methylation events between the groups occurred in genes associated with nuclear functions, such as DNA binding and transcriptional regulation. The present study reports select, genome-wide DNA methylation changes after status epilepticus and in epileptic tolerance, which may contribute to regulating the gene expression environment of the seizure-damaged hippocampus.

show abstract

“…By favoring a more compact chromatin state, the PcG complex proteins appear to function as transcriptional repressors. Among the many genes that they repress, specific subtypes of potassium channels, such as KCNA5 and KCNB2, have been identified [20]. Repression of potassium channels not only leads to decreased consumption of adenosine triphosphate (ATP) (via decreased dependence and utilization of the Na + /K + ATPase to maintain potassium gradients), but can also lead to prolonged action potentials and increased conduction velocity.…”

Section: Introductionmentioning

confidence: 99%

The Epigenetics of Stroke Recovery and Rehabilitation: From Polycomb to Histone Deacetylases

et al. 2013

View full text Add to dashboard Cite

Classical de-afferentation studies, as well as experience-dependent visual plasticity paradigms, have confirmed that both the developing and adult nervous system are capable of unexpected levels of plasticity. This capacity is underscored by the significant spontaneous recovery that can occur in patients with mild-to-moderate impairment following stroke. An evolving model is that an interaction of biological and environmental factors during all epochs post-stroke influences the extent and quality of this plasticity. Here, we discuss data that have implicated specific epigenetic proteins as integrators of environmental influences in 3 aspects of stroke recovery: spontaneous impairment reduction in humans; peri-infarct rewiring in animals as a paradigm for developing therapeutically-driven impairment reduction beyond natural spontaneous recovery; and, finally, classical hippocampal learning and memory paradigms that are theoretically important in skill acquisition for both impairment reduction and compensatory strategies in the rehabilitation setting. Our discussion focuses primarily on B lymphoma Mo-MLV1 insertion region proteins of the polycomb repressive complex, alpha thalassemia/mental retardation syndrome X-linked chromatin remodeling factors, and the best known and most dynamic gene repressors, histone deacetylases. We will highlight exciting current data associated with these proteins and provide promising speculation about how they can be manipulated by drugs, biologics, or noninvasive stimulation for stroke recovery.

show abstract

Polycomb Group Proteins as Epigenetic Mediators of Neuroprotection in Ischemic Tolerance

Cited by 93 publications

References 40 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

Differential DNA Methylation Patterns Define Status Epilepticus and Epileptic Tolerance

The Epigenetics of Stroke Recovery and Rehabilitation: From Polycomb to Histone Deacetylases

Contact Info

Product

Resources

About