Differential Deployment of REST and CoREST Promotes Glial Subtype Specification and Oligodendrocyte Lineage Maturation

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a master transcriptional regulator that binds to numerous genomic RE1 sites where it acts as a molecular scaffold for dynamic recruitment of modulatory and epigenetic cofactors, including corepressor for element-1-silencing transcription factor (CoREST). CoREST also acts as a hub for various cofactors that play important roles in epigenetic remodeling and transcriptional regulation. While REST can recruit CoREST to its macromolecular complex, CoREST complexes also function at genomic sites independently of REST. REST and CoREST perform a broad array of context-specific functions, which include repression of neuronal differentiation genes in neural stem cells (NSCs) and other non-neuronal cells as well as promotion of neurogenesis. Despite their involvement in multiple aspects of neuronal development, REST and CoREST are not believed to have any direct modulatory roles in glial cell maturation.We challenged this view by performing the first study of REST and CoREST in NSC-mediated glial lineage specification and differentiation. Utilizing ChIP on chip (ChIP-chip) assays, we identified distinct but overlapping developmental stage-specific profiles for REST and CoREST target genes during astrocyte (AS) and oligodendrocyte (OL) lineage specification and OL lineage maturation and myelination, including many genes not previously implicated in glial cell biology or linked to REST and CoREST regulation. Amongst these factors are those implicated in macroglial (AS and OL) cell identity, maturation, and maintenance, such as members of key developmental signaling pathways and combinatorial transcription factor codes.Our results imply that REST and CoREST modulate not only neuronal but also glial lineage elaboration. These factors may therefore mediate critical developmental processes including the coupling of neurogenesis and gliogenesis and neuronal-glial interactions that underlie synaptic and neural network plasticity and homeostasis in health and in specific neurological disease states

In vivo NMR as a tool for probing molecular structure and dynamics in intact Chlamydomonas reinhardtii cells

Solid state NMR/Biophysical Organic Chemistr

CKLF1 Aggravates Focal Cerebral Ischemia Injury at Early Stage Partly by Modulating Microglia/Macrophage Toward M1 Polarization Through CCR4

CKLF1 is a chemokine with increased expression in ischemic brain, and targeting CKLF1 has shown therapeutic effects in cerebral ischemia model. Microglia/macrophage polarization is a mechanism involved in poststroke injury expansion. Considering the quick and obvious response of CKLF1 and expeditious evolution of stroke lesions, we focused on the effects of CKLF1 on microglial/macrophage polarization at early stage of ischemic stroke (IS). The present study is to investigate the CKLF1-mediated expression of microglia/macrophage phenotypes in vitro and in vivo, discussing the involved pathway. Primary microglia culture was used in vitro, and mice transient middle cerebral artery occlusion (MCAO) model was adopted to mimic IS. CKLF1 was added to the primary microglia for 24h, and we found that CKLF1 modulated primary microglia skew toward M1 phenotype. In mice transient IS model, CKLF1 was stereotactically microinjected to the lateral ventricle of ischemic hemisphere. CKLF1 aggravated ischemic injury, accompanied by promoting microglia/macrophage toward M1 phenotypic polarization. Increased expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines were observed in mice subjected to cerebral ischemia and administrated with CKLF1. CKLF1(-/-) mice were used to confirm the effects of CKLF1. CKLF1(-/-) mice showed lighter cerebral damage and decreased M1 phenotype of microglia/macrophage compared with the WT control subjected to cerebral ischemia. Moreover, NF-B activation enhancement was detected in CKLF1 treatment group. Our results demonstrated that CKLF1 is an important mediator that skewing microglia/macrophage toward M1 phenotype at early stage of cerebral ischemic injury, which further deteriorates followed inflammatory response, contributing to early expansion of cerebral ischemia injury. Targeting CKLF1 may be a novel way for IS therapy