Conditional knock out of transcription factor CTCF in excitatory neurons induces cognitive deficiency

Choi, Dong Il; Kim, Myeongwon; Kim, Somi; Yu, Nam-Kyung; Kwak, Chuljung; Seo, Hyunhyo; Lee, Kyung-Min; Kaang, Bong‐Kiun

doi:10.1186/s13041-020-00716-z

Cited by 23 publications

(13 citation statements)

References 15 publications

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“…As found for V1396M, Y1385C also favors channel opening by voltage (gain-of-function) [ 21 ]. However, Y1385C has the contrary effect on Ca V 2.1 current density, which is strongly reduced by the mutation without alteration of channel trafficking to the cell membrane (loss-of-function) [ 21 ]. Besides, Y1385C also reduces the voltage threshold for channel inactivation (loss-of-function).…”

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

“…The functional consequences of a third mutation at the S5 segment of Ca V 2.1 domain III, Y1385C, has been recently reported and both gain- and loss-of-function effects have been observed [ 21 ]. As found for V1396M, Y1385C also favors channel opening by voltage (gain-of-function) [ 21 ]. However, Y1385C has the contrary effect on Ca V 2.1 current density, which is strongly reduced by the mutation without alteration of channel trafficking to the cell membrane (loss-of-function) [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Besides, Y1385C also reduces the voltage threshold for channel inactivation (loss-of-function). Nevertheless, the combination of all these alterations results in a global gain-of-function due to higher persistent activity when compared to WT channels, which can lead to a greater Ca 2+ influx into cells over a physiologically relevant window of membrane potentials near the resting potential [ 21 ]. This is consistent with the association of Y1385C to HM, which is produced by CACNA1A gain-of-function mutations [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

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CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings

Martinez‐Monseny

Edo

Casas‐Alba

et al. 2021

IJMS

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The CACNA1A gene encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 Ca2+ channel, essential in neurotransmission, especially in Purkinje cells. Mutations in CACNA1A result in great clinical heterogeneity with progressive symptoms, paroxysmal events or both. During infancy, clinical and neuroimaging findings may be unspecific, and no dysmorphic features have been reported. We present the clinical, radiological and evolutionary features of three patients with congenital ataxia, one of them carrying a new variant. We report the structural localization of variants and their expected functional consequences. There was an improvement in cerebellar syndrome over time despite a cerebellar atrophy progression, inconsistent response to acetazolamide and positive response to methylphenidate. The patients shared distinctive facial gestalt: oval face, prominent forehead, hypertelorism, downslanting palpebral fissures and narrow nasal bridge. The two α1A affected residues are fully conserved throughout evolution and among the whole human CaV channel family. They contribute to the channel pore and the voltage sensor segment. According to structural data analysis and available functional characterization, they are expected to exert gain- (F1394L) and loss-of-function (R1664Q/R1669Q) effect, respectively. Among the CACNA1A-related phenotypes, our results suggest that non-progressive congenital ataxia is associated with developmental delay and dysmorphic features, constituting a recognizable syndromic neurodevelopmental disorder.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings

Martinez‐Monseny

Edo

Casas‐Alba

et al. 2021

IJMS

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“…The two-tailed GSEA (GSEA-2T) is used to check if the regulon is positively or negatively associated with the gene expression and finally assesses their significance expression meaning that a large positive enrichment score (ES) represents an activated regulon, whereas a large negative ES represents a repressed regulon. We used a list of 17 TFs ( CREB, MEF2, Npas4, SRF, CTCF, TCF4, DREAM, KChIP3, MeCP2, FOXP2, ZNF, SP3, ptf1a, REST, OTX2, XBP1, FOXO ) which have already been discussed in relation to cognitive function (Manolopoulos et al, 2010 ; Wang and Konopka, 2013 ; Nonaka et al, 2014 ; Mozzi et al, 2017 ; Hwang and Zukin, 2018 ; Xiao et al, 2018 ; Badowska et al, 2020 ; Choi et al, 2021 ) and performed GSEA-2T with a default p -value cut-off set to 0.05 and using 10,000 permutations to identify significant regulons associated with cognitive function in our gene expression data ( https://bioconductor.org/packages/devel/bioc/vignettes/RTN/inst/doc/RTN.html ).…”

Section: Methodsmentioning

confidence: 99%

Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins

Mohammadnejad

Lund

et al. 2021

Front. Genet.

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Cognitive aging is one of the major problems worldwide, especially as people get older. This study aimed to perform global gene expression profiling of cognitive function to identify associated genes and pathways and a novel transcriptional regulatory network analysis to identify important regulons. We performed single transcript analysis on 400 monozygotic twins using an assumption-free generalized correlation coefficient (GCC), linear mixed-effect model (LME) and kinship model and identified six probes (one significant at the standard FDR < 0.05 while the other results were suggestive with 0.18 ≤ FDR ≤ 0.28). We combined the GCC and linear model results to cover diverse patterns of relationships, and meaningful and novel genes like APOBEC3G, H6PD, SLC45A1, GRIN3B, and PDE4D were detected. Our exploratory study showed the downregulation of all these genes with increasing cognitive function or vice versa except the SLC45A1 gene, which was upregulated with increasing cognitive function. Linear models found only H6PD and SLC45A1, the other genes were captured by GCC. Significant functional pathways (FDR < 3.95e-10) such as focal adhesion, ribosome, cysteine and methionine metabolism, Huntington's disease, eukaryotic translation elongation, nervous system development, influenza infection, metabolism of RNA, and cell cycle were identified. A total of five regulons (FDR< 1.3e-4) were enriched in a transcriptional regulatory analysis in which CTCF and REST were activated and SP3, SRF, and XBP1 were repressed regulons. The genome-wide transcription analysis using both assumption-free GCC and linear models identified important genes and biological pathways implicated in cognitive performance, cognitive aging, and neurological diseases. Also, the regulatory network analysis revealed significant activated and repressed regulons on cognitive function.

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Fibrils Emerging from Droplets: Molecular Guiding Principles behind Phase Transitions of a Short Peptide‐Based Condensate Studied by Solid‐State NMR**

Lipiński

Zehnder

Abbas

et al. 2023

Chemistry A European J

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Biochemical reactions occurring in highly crowded cellular environments require different means of control to ensure productivity and specificity. Compartmentalization of reagents by liquid‐liquid phase separation is one of these means. However, extremely high local protein concentrations of up to 400 mg/ml can result in pathological aggregation into fibrillar amyloid structures, a phenomenon that has been linked to various neurodegenerative diseases. Despite its relevance, the process of liquid‐to‐solid transition inside condensates is still not well understood at the molecular level. We thus herein use small peptide derivatives that can undergo both liquid‐liquid and subsequent liquid‐to‐solid phase transition as model systems to study both processes. Using solid‐state nuclear magnetic resonance (NMR) and transmission electron microscopy (TEM), we compare the structure of condensed states of leucine, tryptophan and phenylalanine containing derivatives, distinguishing between liquid‐like condensates, amorphous aggregates and fibrils, respectively. A structural model for the fibrils formed by the phenylalanine derivative was obtained by an NMR‐based structure calculation. The fibrils are stabilised by hydrogen bonds and side‐chain π‐π interactions, which are likely much less pronounced or absent in the liquid and amorphous state. Such noncovalent interactions are equally important for the liquid‐to‐solid transition of proteins, particularly those related to neurodegenerative diseases.

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Conditional knock out of transcription factor CTCF in excitatory neurons induces cognitive deficiency

Cited by 23 publications

References 15 publications

CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings

CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings

Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins

Fibrils Emerging from Droplets: Molecular Guiding Principles behind Phase Transitions of a Short Peptide‐Based Condensate Studied by Solid‐State NMR**

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