112 research outputs found
Differential binding of non-canonical histone variant H2A.Z & its de-acetylation is evident in enhanced cognitive function
No full textAlthough histone modifications and DNA methylation have been meticulously studied in the context of learning & memory formation, very few studies have demonstrated non-canonical histone variants as potential regulators of memory formation. Compared to canonical histones, these histone variants are expressed independently of DNA replication and are important for many physiological events as they confer altered chromatin structures, thereby regulating transcription. Recently, H2A.Z (variant of canonical histone, H2A) has been reported as a novel epigenetic regulator in memory formation (Zovkic et. al. 2014), which raised the question, whether differential binding of H2A.Z or its modification (e.g acetylation) across the whole genome could be a stable modulator for life-long memory acquisition and cognition. Here, we investigated genomic regions bound by H2A.Z and its acetylated variant (H2A.Zac) using chromatin immunoprecipitation followed by sequencing (ChIP-seq) in FACS-sorted neuronal and nonneuronal nuclei from hippocampal CA1 region. Initially, mRNA levels of H2afz (gene of H2A.Z) were assessed in CA1 region of aged (16 months old) and Alzheimer’s model mice (5XFAD) comparing them to young (3 months old) and wild type mice respectively. Furthermore, ChIP protocols for H2A.Z and H2A.Zac were optimized, as it has not been done before in this context. As a model of enhanced cognition, hippocampal CA1 regions from mice subjected to 4 months enriched environment (EE) were used for ChIP-seq against H2A.Z and H2A.Zac, comparing to home caged animals as controls. ChIP-seq analysis showed decreased binding of H2A.Z and its de-acetylation at specific promoter regions in CA1 neurons upon environmental enrichment. Promoters with decreased binding or decreased acetylation were found to be involved in genes functionally associated with neurogenesis, synaptic plasticity and several biosynthetic pathways. Further study is needed to prove their effect on transcription of those genes
Differential binding of non-canonical histone variant H2A.Z & its de-acetylation is evident in enhanced cognitive function
No full textAlthough histone modifications and DNA methylation have been meticulously studied in the context of learning & memory formation, very few studies have demonstrated non-canonical histone variants as potential regulators of memory formation. Compared to canonical histones, these histone variants are expressed independently of DNA replication and are important for many physiological events as they confer altered chromatin structures, thereby regulating transcription. Recently, H2A.Z (variant of canonical histone, H2A) has been reported as a novel epigenetic regulator in memory formation (Zovkic et. al. 2014), which raised the question, whether differential binding of H2A.Z or its modification (e.g acetylation) across the whole genome could be a stable modulator for life-long memory acquisition and cognition. Here, we investigated genomic regions bound by H2A.Z and its acetylated variant (H2A.Zac) using chromatin immunoprecipitation followed by sequencing (ChIP-seq) in FACS-sorted neuronal and nonneuronal nuclei from hippocampal CA1 region. Initially, mRNA levels of H2afz (gene of H2A.Z) were assessed in CA1 region of aged (16 months old) and Alzheimer’s model mice (5XFAD) comparing them to young (3 months old) and wild type mice respectively. Furthermore, ChIP protocols for H2A.Z and H2A.Zac were optimized, as it has not been done before in this context. As a model of enhanced cognition, hippocampal CA1 regions from mice subjected to 4 months enriched environment (EE) were used for ChIP-seq against H2A.Z and H2A.Zac, comparing to home caged animals as controls. ChIP-seq analysis showed decreased binding of H2A.Z and its de-acetylation at specific promoter regions in CA1 neurons upon environmental enrichment. Promoters with decreased binding or decreased acetylation were found to be involved in genes functionally associated with neurogenesis, synaptic plasticity and several biosynthetic pathways. Further study is needed to prove their effect on transcription of those genes
Loss of HDAC5 impairs memory function : implications for Alzheimer's disease
No full textEpigenetic mechanisms such as histone-acetylation have been implicated with learning and memory and are believed to contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Histone-deacetylase (HDAC) inhibitors were shown to exhibit neuroprotective and neurodegenerative properties in AD animal models, and targeting HDACs appears to be a promising therapeutic strategy for brain diseases. The role of the distinct HDAC proteins in the adult brain is, however, not well understood and so far only pan-HDAC inhibitors have been tested in preclinical settings. Understanding the role of individual HDACs in cognition and AD pathogenesis is therefore vital to develop more selective HDAC inhibitors for the treatment of AD. In this study we investigated the role of HDAC5 in memory function and AD pathogenesis. We show that loss of HDAC5 impairs memory function but has little impact on pathogenesis in a mouse model for amyloid pathology. Our data reveals a novel role of HDAC5 in memory consolidation and shows that future approaches to develop more selective HDAC inhibitors for the treatment of AD should avoid targeting HDAC5
Histone-Methyltransferases MLL1 (KMT2A) and MLL2 (KMT2B) are important for learning and memory in mice
No full textHistone-Methyltransferases MLL1 (KMT2A) and MLL2 (KMT2B) are important for learning and memory in mice
No full textCemil Kavukçu as a novelist
No full textCemil Kavukçu, 1980 sonrası gelişen Türk edebiyatının önemli yazarlarından biridir. Öykü, roman, deneme, anı, çocuk edebiyatı gibi türlerde eserler veren sanatçı, daha çok öykü türünde kaleme aldığı eserleriyle tanmış ve "öykücü" sıfatına mazhar olmuştur. Üretken bir yazar olan Cemil Kavukçu, eserlerinde kullandığı dil ve üslup açısından Sait Faik, Memduh Şevket Esendal, Oğuz Atay gibi isimlerin etkisinde kalır. Bunun yanında, edebiyatımızın birçok türünde eser verebilecek yetkinliğe ve bakış açısına sahip olan Kavukçu'nun daha çok öykü türünde kaleme aldığı metinleri inceleme ve araştırma konusu edilmiştir. Bu durum, yazarın "romancı" kimliğinin arka planda kalmasına neden olmuştur. Cemil Kavukçu, 1998 yılından itibaren Dönüş romanıyla, altı öykü kitabından sonra yeni bir türe geçiş yapar. Dönüş'ün ardından 2004 yılında Suda Bulanık Oyunlar'ı kaleme alan yazar, 2005 yılının Aralık ayında yayımladığı Gamba romanıyla kendisi için yeni bir tür olan romanda olgunlaşma evresine geçer. Yazarın Türk edebiyatı ekseninde, öykü türündeki başarısı yadsınamaz bir gerçektir. Fakat, Kavukçu'yu tek bir tür yazarı olarak düşünmek, kendisine ve yazarlığına bir haksızlık oluşturur. Nitekim, onun üç romanı olan Dönüş, Suda Bulanık Oyunlar ve Gamba romanını, bilimsel ve edebî açıdan incelemek, edebiyat tarihimiz ve yazarın romancı kimliği açısından önemlidir. Bu açıdan bakıldığında, araştırmamızın konusu, yüksek lisans tezine başlığını veren Cemil Kavukçu'nun romancı yönü ve romanları olacaktır. Çalışmamızın giriş bölümünde, öncelikli olarak Batı edebiyatında roman türünün doğuşu ve gelişiminden söz edilecektir. Arkasından roman türünün Türk edebiyatındaki tarihi seyri üzerinde durulacaktır. Giriş kısmında, özellikle Cemil Kavukçu'nun içerisinde bulunduğu 1980 sonrası Türk romanı, modern/postmodern roman kavramları üzerinde durulacaktır. Birinci bölümde ise, ilk etapta, Cemil Kavukçu'nun yaşamı üzerinden doğumuna, çocukluk ve gençlik yıllarına, ailesine, evliliğine ve iş hayatına değinilecektir. Bu kısımlarda, sanatçının yazarlığını ve edebî kişiliğini etkileyen unsurlardan söz edilecektir. Ardından Kavukçu'nun edebî kişiliği açıklanacak ve son olarak yapıtlarına yer verilecektir. İkinci bölümde, tezin asıl inceleme konusunu oluşturan, Cemil Kavukçu'nun kaleme aldığı Dönüş, Suda Bulanık Oyunlar ve Gamba romanları üzerinde durulacaktır. Romanların detaylı ve sistemli bir şekilde tahlili yapılacak, Kavukçu'nun romancı hüviyeti ortaya konacaktır. Tahlil esnasında, bilimsel ve edebî açıdan Şerif Aktaş'ın ve Nurullah Çetin'in roman çözümleme yöntemlerinden yararlanılacaktır. Anahtar Kelimeler: Cemil Kavukçu, roman, tahlil, Dönüş, Suda Bulanık Oyunlar, GambaCemil Kavukçu is one of the important writers of Turkish literature that developed after 1980. The artist, who produced works in genres such as short stories, novels, essays, memoirs, and children's literature, was known for his works in the genre of short stories and earned the title of "storyteller". A prolific writer, Cemil Kavukçu was influenced by names such as Sait Faik, Memduh Şevket Esendal, and Oğuz Atay in terms of the language and style he used in his works. In addition, the texts written by Kavukçu, who has the competence and perspective of producing works in many genres of our literature, have been the subject of examination and research. This situation caused the author's "novelist" identity to remain in the background. Cemil Kavukçu switched to a new genre after 6 storybooks with his novel Dönüş since 1998.The author, who wrote Suda Bulanık Oyunlar in 2004 after Dönüş, enters the maturation phase in a novel that is a new genre for him, with the novel Gamba published in December 2005. It is an undeniable fact that the author's success in the genre of short stories on the axis of Turkish literature. However, to think of Kavukçu as a single genre writer would be unfair to him and his authorship. As a matter of fact, examining his three novels, Dönüş, Suda Bulanık Oyunlar and Gamba from a scientific and literary perspective is important for our literary history and the novelist identity of the author. From this point of view, the subject of our research will be the novelist aspect and novels of Cemil Kavukçu, who gave the title to his master's thesis. In the introductory part of our study, first of all, the birth and development of the novel genre in Western literature will be mentioned.Then, the historical course of the novel genre in Turkish literature will be emphasized. In the introduction, the post-1980 Turkish novel, in which Cemil Kavukçu is in particular, and the concepts of modern/postmodern novel will be emphasized. In the first part, in the first place, Cemil Kavukçu's birth, childhood and youth years, family, marriage and business life will be discussed. In these parts, the factors affecting the authorship and literary personality of the artist will be mentioned. Then, Kavukçu's literary personality will be explained and finally his works will be included. In the second part, the main subject of the thesis will be focused on the novels Dön, Suda Bulanık Oyunlar and Gamba written by Cemil Kavukçu. The novels will be analyzed in a detailed and systematic way, and Kavukçu's novelist identity will be revealed.During the analysis, scientific and literary analysis methods of Şerif Aktaş and Nurullah Çetin will be used. Keywords: Cemil Kavukçu, novel, analysis, Dönüş, Suda Bulanık Oyunlar, Gamb
Conditional Loss of BAF (mSWI/SNF) Scaffolding Subunits Affects Specification and Proliferation of Oligodendrocyte Precursors in Developing Mouse Forebrain
No full textOligodendrocytes are responsible for axon myelination in the brain and spinal cord. Generation of oligodendrocytes entails highly regulated multistage neurodevelopmental events, including proliferation, differentiation and maturation. The chromatin remodeling BAF (mSWI/SNF) complex is a notable regulator of neural development. In our previous studies, we determined the indispensability of the BAF complex scaffolding subunits BAF155 and BAF170 for neurogenesis, whereas their role in gliogenesis is unknown. Here, we show that the expression of BAF155 and BAF170 is essential for the genesis of oligodendrocytes during brain development. We report that the ablation of BAF155 and BAF170 in the dorsal telencephalic (dTel) neural progenitors or in oligodendrocyte-producing progenitors in the ventral telencephalon (vTel) in double-conditional knockout (dcKO) mouse mutants, perturbed the process of oligodendrogenesis. Molecular marker and cell cycle analyses revealed impairment of oligodendrocyte precursor specification and proliferation, as well as overt depletion of oligodendrocytes pool in dcKO mutants. Our findings unveil a central role of BAF155 and BAF170 in oligodendrogenesis, and thus substantiate the involvement of the BAF complex in the production of oligodendrocytes in the forebrain.Oligodendrocytes are responsible for axon myelination in the brain and spinal cord. Generation of oligodendrocytes entails highly regulated multistage neurodevelopmental events, including proliferation, differentiation and maturation. The chromatin remodeling BAF (mSWI/SNF) complex is a notable regulator of neural development. In our previous studies, we determined the indispensability of the BAF complex scaffolding subunits BAF155 and BAF170 for neurogenesis, whereas their role in gliogenesis is unknown. Here, we show that the expression of BAF155 and BAF170 is essential for the genesis of oligodendrocytes during brain development. We report that the ablation of BAF155 and BAF170 in the dorsal telencephalic (dTel) neural progenitors or in oligodendrocyte-producing progenitors in the ventral telencephalon (vTel) in double-conditional knockout (dcKO) mouse mutants, perturbed the process of oligodendrogenesis. Molecular marker and cell cycle analyses revealed impairment of oligodendrocyte precursor specification and proliferation, as well as overt depletion of oligodendrocytes pool in dcKO mutants. Our findings unveil a central role of BAF155 and BAF170 in oligodendrogenesis, and thus substantiate the involvement of the BAF complex in the production of oligodendrocytes in the forebrain.Open-Access-Publikationsfonds 202
H3 Acetylation-Induced Basal Progenitor Generation and Neocortex Expansion Depends on the Transcription Factor Pax6
No full textEnrichment of basal progenitors (BPs) in the developing neocortex is a central driver of cortical enlargement. The transcription factor Pax6 is known as an essential regulator in generation of BPs. H3 lysine 9 acetylation (H3K9ac) has emerged as a crucial epigenetic mechanism that activates the gene expression program required for BP pool amplification. In this current work, we applied immunohistochemistry, RNA sequencing, chromatin immunoprecipitation and sequencing, and the yeast two-hybrid assay to reveal that the BP-genic effect of H3 acetylation is dependent on Pax6 functionality in the developing mouse cortex. In the presence of Pax6, increased H3 acetylation caused BP pool expansion, leading to enhanced neurogenesis, which evoked expansion and quasi-convolution of the mouse neocortex. Interestingly, H3 acetylation activation exacerbates the BP depletion and corticogenesis reduction effect of Pax6 ablation in cortex-specific Pax6 mutants. Furthermore, we found that H3K9 acetyltransferase KAT2A/GCN5 interacts with Pax6 and potentiates Pax6-dependent transcriptional activity. This explains a genome-wide lack of H3K9ac, especially in the promoter regions of BP-genic genes, in the Pax6 mutant cortex. Together, these findings reveal a mechanistic coupling of H3 acetylation and Pax6 in orchestrating BP production and cortical expansion through the promotion of a BP gene expression program during cortical development
RNA-Dependent Intergenerational Inheritance of Enhanced Synaptic Plasticity after Environmental Enrichment
No full textSummary: Physical exercise in combination with cognitive training is known to enhance synaptic plasticity, learning, and memory and lower the risk for various complex diseases including Alzheimer’s disease. Here, we show that exposure of adult male mice to an environmental enrichment paradigm leads to enhancement of synaptic plasticity and cognition also in the next generation. We show that this effect is mediated through sperm RNA and especially miRs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific miRs as candidates mechanistically involved in this type of transmission. : Environmental enrichment (EE), a combination of physical and mental exercise, has been shown to increase cognitive abilities in mice and in humans. Benito et al. find that offspring of male mice subjected to EE also show this increase. This effect is dependent on sperm RNA and involves microRNA212/132. Keywords: epigenetics, brain, microRNA, memory, intergenerational, transgenerational, exercise, environmental enrichment, cognitio
Loss of BAF Complex in Developing Cortex Perturbs Radial Neuronal Migration in a WNT Signaling-Dependent Manner
No full textRadial neuronal migration is a key neurodevelopmental event indispensable for proper cortical laminar organization. Cortical neurons mainly use glial fiber guides, cell adhesion dynamics, and cytoskeletal remodeling, among other discrete processes, to radially trek from their birthplace to final layer positions. Dysregulated radial migration can engender cortical mis-lamination, leading to neurodevelopmental disorders. Epigenetic factors, including chromatin remodelers have emerged as formidable regulators of corticogenesis. Notably, the chromatin remodeler BAF complex has been shown to regulate several aspects of cortical histogenesis. Nonetheless, our understanding of how BAF complex regulates neuronal migration is limited. Here, we report that BAF complex is required for neuron migration during cortical development. Ablation of BAF complex in the developing mouse cortex caused alteration in the cortical gene expression program, leading to loss of radial migration-related factors critical for proper cortical layer formation. Of note, BAF complex inactivation in cortex caused defective neuronal polarization resulting in diminished multipolar-to-bipolar transition and eventual disruption of radial migration of cortical neurons. The abnormal radial migration and cortical mis-lamination can be partly rescued by downregulating WNT signaling hyperactivity in the BAF complex mutant cortex. By implication, the BAF complex modulates WNT signaling to establish the gene expression program required for glial fiber-dependent neuronal migration, and cortical lamination. Overall, BAF complex has been identified to be crucial for cortical morphogenesis through instructing multiple aspects of radial neuronal migration in a WNT signaling-dependent manner.Radial neuronal migration is a key neurodevelopmental event indispensable for proper cortical laminar organization. Cortical neurons mainly use glial fiber guides, cell adhesion dynamics, and cytoskeletal remodeling, among other discrete processes, to radially trek from their birthplace to final layer positions. Dysregulated radial migration can engender cortical mis-lamination, leading to neurodevelopmental disorders. Epigenetic factors, including chromatin remodelers have emerged as formidable regulators of corticogenesis. Notably, the chromatin remodeler BAF complex has been shown to regulate several aspects of cortical histogenesis. Nonetheless, our understanding of how BAF complex regulates neuronal migration is limited. Here, we report that BAF complex is required for neuron migration during cortical development. Ablation of BAF complex in the developing mouse cortex caused alteration in the cortical gene expression program, leading to loss of radial migration-related factors critical for proper cortical layer formation. Of note, BAF complex inactivation in cortex caused defective neuronal polarization resulting in diminished multipolar-to-bipolar transition and eventual disruption of radial migration of cortical neurons. The abnormal radial migration and cortical mis-lamination can be partly rescued by downregulating WNT signaling hyperactivity in the BAF complex mutant cortex. By implication, the BAF complex modulates WNT signaling to establish the gene expression program required for glial fiber-dependent neuronal migration, and cortical lamination. Overall, BAF complex has been identified to be crucial for cortical morphogenesis through instructing multiple aspects of radial neuronal migration in a WNT signaling-dependent manner
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