Mechanism of REST/NRSF regulation of clustered protocadherin α genes.
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ABSTRACT:
SUBMITTER: Tang Y
PROVIDER: S-EPMC8096226 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Repressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5-1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDH alpha genes. Thus, REST/NRSF represses PCDH alpha gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.
2021-04-14 | GSE150254 | GEO
Project description:Mechanism of REST/NRSF Regulation of Clustered Protocadherin Alpha Genes
| PRJNA631681 | ENA
Project description:Advanced paternal age can have deleterious effects on various traits in the next generation. Here, we establish a paternal-aging model in mice to understand the molecular mechanisms of transgenerational epigenetics. Whole-genome target DNA methylome analyses of sperm from aged mice reveal more hypo-methylated genomic regions enriched in REST/NRSF binding motifs. Gene set enrichment analyses also reveal the upregulation of REST/NRSF target genes in the forebrain of embryos from aged fathers. Offspring derived from young mice administrated with a DNA de-methylation drug phenocopy the abnormal vocal communication of pups derived from aged fathers. In conclusion, hypo-methylation of sperm DNA can be a key molecular feature modulating neurodevelopmental programs in offspring by causing fluctuations in the expression of REST/NRSF target genes.
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Project description:The cadherin family is classified into classical cadherins, desmosomal cadherins and protocadherins (PCDHs). Genomic structures distinguish between PCDHs and other cadherins, and between clustered and non-clustered PCDHs. The phylogenetic analysis with full sequences of non-clustered PCDHs enabled them to be further classified into three subgroups: δ1 (PCDH1, PCDH7, PCDH9, PCDH11 and PCDH20), δ2 (PCDH8, PCDH10, PCDH12, PCDH17, PCDH18 and PCDH19) and ε (PCDH15, PCDH16, PCDH21 and MUCDHL). ε-PCDH members except PCDH21 have either higher or lower numbers of cadherin repeats than those of other PCDHs. Non-clustered PCDHs are expressed predominantly in the nervous system and have spatiotemporally diverse expression patterns. Especially, the region-specific expressions of non-clustered PCDHs have been observed in cortical area of early postnatal stage and in caudate putaman and/or hippocampal formation of mature brains, suggesting that non-clustered PCDHs play roles in the circuit formation and maintenance. The non-clustered PCDHs appear to have homophilic/heterophilc cell-cell adhesion properties, and each member has diverse cell signaling partnership distinct from those of other members (PCDH7/TAF1; PCDH8/TAO2β; PCDH10/Nap1; PCDH11/β-catenin; PCDH18/mDab1). Furthermore, each PCDH has several isoforms with differential cytoplasmic sequences, suggesting that one PCDH isoform could activate intracellular signaling differential from other isoforms. These facts suggest that non-clustered PCDHs play roles as a mediator of a regulator of other molecules as well as cell-cell adhesion. Furthermore, some non-clustered PCDHs have been considered to be involved in neuronal diseases such as autism-spectrum disorders, schizophrenia, and female-limited epilepsy and cognitive impairment, suggesting that they play multiple, tightly regulated roles in normal brain function. In addition, some non-clustered PCDHs have been suggested as candidate tumor suppressor genes in several tissues. Although molecular adhesive and regulatory properties of some PCDHs began to be unveiled, the endeavor to understand the molecular mechanism of non-clustered PCDH is still in its infancy and requires future study.
| S-EPMC3084973 | biostudies-literature
Project description:To explain the mechanism for specifying diverse neuronal connections in the brain, Sperry proposed that individual cells carry chemoaffinity tags on their surfaces. The enormous complexity of these connections requires a tremendous diversity of cell-surface proteins. A large number of neural transmembrane protocadherin (Pcdh) proteins is encoded by three closely linked human and mouse gene clusters (alpha, beta, and gamma). To gain insight into Pcdh evolution, I performed comprehensive comparative cDNA and genomic DNA analyses for the three clusters in the chimpanzee, rat, and zebrafish genomes. I found that there are species-specific duplications in vertebrate Pcdh genes and that additional diversity is generated through alternative splicing within the zebrafish "variable" and "constant" regions. Moreover, different codons (sites) in the mammalian Pcdh ectodomains (ECs) are under diversifying selection, with some under diversity-enhancing positive Darwinian selection and others, including calcium-binding sites, under strong purifying selection. Interestingly, almost all positively selected codon positions are located on the surface of ECs 2 and 3. These diversified residues likely play an important role in combinatorial interactions of Pcdh proteins, which could provide the staggering diversity required for neuronal connections in the brain. These results also suggest that adaptive selection is an additional evolutionary factor for increasing Pcdh diversity.
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Project description:The brain is a large and complex network of neurons. Specific neuronal connectivity is thought to be based on the combinatorial expression of the 52 protocadherins (Pcdh) membrane adhesion proteins, whereby each neuron expresses only a specific subset. Pcdh genes are arranged in tandem, in a cluster of three families: Pcdhα, Pcdhβ and Pcdhγ. The expression of each Pcdh gene is regulated by a promoter that has a regulatory conserved sequence element (CSE), common to all 52 genes. The mechanism and factors controlling individual Pcdh gene expression are currently unknown. Here we show that the promoter of each Pcdh gene contains a gene-specific conserved control region, termed specific sequence element (SSE), located adjacent and upstream to the CSE and activates transcription together with the CSE. We purified the complex that specifically binds the SSE-CSE region and identified the CCTC binding-factor (CTCF) as a key molecule that binds and activates Pcdh promoters. Our findings point to CTCF as a factor essential for Pcdh expression and probably governing neuronal connectivity.
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Project description:The spatial and temporal control of gene expression is key to generation of specific cellular fates during development. Studies of the transcriptional repressor REST/NRSF (RE1 Silencing Transcription Factor or Neural Restrictive Silencing Factor) have provided important insight into the role that epigenetic modifications play in differential gene expression. However, the precise function of REST during embryonic development is not well understood. We have discovered a novel interaction between zebrafish Rest and the Hedgehog (Hh) signaling pathway. We observed that Rest knockdown enhances or represses Hh signaling in a context-dependant manner. In wild-type embryos and embryos with elevated Hh signaling, Rest knockdown augments transcription of Hh target genes. Conversely, in contexts where Hh signaling is diminished, Rest knockdown has the opposite effect and Hh target gene expression is further attenuated. Epistatic analysis revealed that Rest interacts with the Hh pathway at a step downstream of Smo. Furthermore, we present evidence implicating the bifunctional, Hh signaling component Gli2a as key to the Rest modulation of the Hh response. The role of Rest as a regulator of Hh signaling has broad implications for many developmental contexts where REST and Hh signaling act.
| S-EPMC2854301 | biostudies-literature
Project description:UnlabelledDuring embryonic development, regulation of gene expression is key to creating the many subtypes of cells that an organism needs throughout its lifetime. Recent work has shown that maternal genetics and environmental factors have lifelong consequences on diverse processes ranging from immune function to stress responses. The RE1-silencing transcription factor (Rest) is a transcriptional repressor that interacts with chromatin-modifying complexes to repress transcription of neural-specific genes during early development. Here we show that in zebrafish, maternally supplied rest regulates expression of target genes during larval development and has lifelong impacts on behavior. Larvae deprived of maternal rest are hyperactive and show atypical spatial preferences. Adult male fish deprived of maternal rest present with atypical spatial preferences in a novel environment assay. Transcriptome sequencing revealed 158 genes that are repressed by maternal rest in blastula stage embryos. Furthermore, we found that maternal rest is required for target gene repression until at least 6 dpf. Importantly, disruption of the RE1 sites in either snap25a or snap25b resulted in behaviors that recapitulate the hyperactivity phenotype caused by absence of maternal rest Both maternal rest mutants and snap25a RE1 site mutants have altered primary motor neuron architecture that may account for the enhanced locomotor activity. These results demonstrate that maternal rest represses snap25a/b to modulate larval behavior and that early Rest activity has lifelong behavioral impacts.Significance statementMaternal factors deposited in the oocyte have well-established roles during embryonic development. We show that, in zebrafish, maternal rest (RE1-silencing transcription factor) regulates expression of target genes during larval development and has lifelong impacts on behavior. The Rest transcriptional repressor interacts with chromatin-modifying complexes to limit transcription of neural genes. We identify several synaptic genes that are repressed by maternal Rest and demonstrate that snap25a/b are key targets of maternal rest that modulate larval locomotor activity. These results reveal that zygotic rest is unable to compensate for deficits in maternally supplied rest and uncovers novel temporal requirements for Rest activity, which has implications for the broad roles of Rest-mediated repression during neural development and in disease states.
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Project description:Clustered protocadherins (Pcdhs) are neuronal cell adhesion molecules characterized by homophilic adhesion between the tetramers of 58 distinct isoforms in mice. The diversity of Pcdhs and resulting highly-specific neuronal adhesion may be required for the formation of neural circuits for executing higher brain functions. However, this hypothesis remains to be tested, because knockout of Pcdh genes produces abnormalities that may interfere with higher brain functions indirectly. In Pcdh-α1,12 mice, only α1, α12 and two constitutive isoforms are expressed out of 14 isoforms. The appearance and behavior of Pcdh-α1,12 mice are similar to those of wild-type mice, and most abnormalities reported in Pcdh-α knockout mice are not present in Pcdh-α1,12 mice. We examined Pcdh-α1,12 mice in detail, and found that cortical depression induced by sensory mismatches between vision and whisker sensation in the visual cortex was impaired. Since Pcdh-α is densely distributed over the cerebral cortex, various types of higher function are likely impaired in Pcdh-α1,12 mice. As expected, visual short-term memory of space/shape was impaired in behavioral experiments using space/shape cues. Furthermore, behavioral learning based on audio-visual associative memory was also impaired. These results indicate that the molecular diversity of Pcdh-α plays essential roles for sensory integration and short-term memory.
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Project description:Clustered protocadherins mediate neuronal self-recognition and non-self discrimination-neuronal "barcoding"-which underpin neuronal self-avoidance in vertebrate neurons. Recent structural, biophysical, computational, and cell-based studies on protocadherin structure and function have led to a compelling molecular model for the barcoding mechanism. Protocadherin isoforms assemble into promiscuous cis-dimeric recognition units and mediate cell-cell recognition through homophilic trans-interactions. Each recognition unit is composed of two arms extending from the membrane proximal EC6 domains. A cis-dimeric recognition unit with each arm coding adhesive trans homophilic specificity can generate a zipper-like assembly that in turn suggests a chain termination mechanism for self-vs-non-self-discrimination among vertebrate neurons.
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