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1.
Stem Cell Reports ; 3(3): 502-15, 2014 Sep 09.
Article in English | MEDLINE | ID: mdl-25241747

ABSTRACT

Signaling factors including retinoic acid (RA) and thyroid hormone (T3) promote neuronal, oligodendrocyte, and astrocyte differentiation of cortical neural stem cells (NSCs). However, the functional specificity of transcriptional repressor checkpoints controlling these differentiation programs remains unclear. Here, we show by genome-wide analysis that histone deacetylase (HDAC)2 and HDAC3 show overlapping and distinct promoter occupancy at neuronal and oligodendrocyte-related genes in NSCs. The absence of HDAC3, but not HDAC2, initiated a neuronal differentiation pathway in NSCs. The ablation of the corepressor NCOR or HDAC2, in conjunction with T3 treatment, resulted in increased expression of oligodendrocyte genes, revealing a direct HDAC2-mediated repression of Sox8 and Sox10 expression. Interestingly, Sox10 was required also for maintaining the more differentiated state by repression of stem cell programming factors such as Sox2 and Sox9. Distinct and nonredundant actions of NCORs and HDACs are thus critical for control of lineage progression and differentiation programs in neural progenitors.


Subject(s)
Co-Repressor Proteins/metabolism , Gene Expression Regulation, Developmental , Histone Deacetylase 2/metabolism , Histone Deacetylases/metabolism , Neural Stem Cells/cytology , Animals , Cells, Cultured , Neural Stem Cells/metabolism , Neurogenesis , Promoter Regions, Genetic , Rats , SOXE Transcription Factors/genetics
2.
Genome Biol ; 14(9): R98, 2013.
Article in English | MEDLINE | ID: mdl-24044525

ABSTRACT

BACKGROUND: Pluripotency is characterized by a unique transcriptional state, in which lineage-specification genes are poised for transcription upon exposure to appropriate stimuli, via a bivalency mechanism involving the simultaneous presence of activating and repressive methylation marks at promoter-associated histones. Recent evidence suggests that other mechanisms, such as RNA polymerase II pausing, might be operational in this process, but their regulation remains poorly understood. RESULTS: Here we identify the non-coding snRNA 7SK as a multifaceted regulator of transcription in embryonic stem cells. We find that 7SK represses a specific cohort of transcriptionally poised genes with bivalent or activating chromatin marks in these cells, suggesting a novel poising mechanism independent of Polycomb activity. Genome-wide analysis shows that 7SK also prevents transcription downstream of polyadenylation sites at several active genes, indicating that 7SK is required for normal transcriptional termination or control of 3'-UTR length. In addition, 7SK suppresses divergent upstream antisense transcription at more than 2,600 loci, including many that encode divergent long non-coding RNAs, a finding that implicates the 7SK snRNA in the control of transcriptional bidirectionality. CONCLUSIONS: Our study indicates that a single non-coding RNA, the snRNA 7SK, is a gatekeeper of transcriptional termination and bidirectional transcription in embryonic stem cells and mediates transcriptional poising through a mechanism independent of chromatin bivalency.


Subject(s)
Embryonic Stem Cells/metabolism , Gene Expression Regulation, Developmental , Genome , RNA Polymerase II/genetics , RNA, Small Nuclear/genetics , Transcription Termination, Genetic , 3' Untranslated Regions , Animals , Binding Sites , Chromatin/chemistry , Chromatin/metabolism , Embryo, Mammalian , Embryonic Stem Cells/cytology , Genetic Loci , Histones/genetics , Histones/metabolism , Mice , Polyadenylation , Promoter Regions, Genetic , RNA Polymerase II/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , RNA, Small Nuclear/antagonists & inhibitors , RNA, Small Nuclear/metabolism
3.
Neurochem Res ; 38(4): 797-806, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23389658

ABSTRACT

Alzheimer's disease, the most prevalent age-related neurodegenerative disease, is characterized by the presence of extracellular senile plaques composed of amyloid-beta (Aß) peptide and intracellular neurofibrillary tangles. More than 50 % of Alzheimer's disease (AD) patients also exhibit abundant accumulation of α-synuclein (α-Syn)-positive Lewy bodies. This Lewy body variant of AD (LBV-AD) is associated with accelerated cognitive dysfunction and progresses more rapidly than pure AD. In addition, it has been suggested that Aß and α-Syn can directly interact. In this study we investigated the effect of α-Syn on Aß-induced toxicity in cortical neurons. In order to mimic the intracellular accumulation of α-Syn observed in the brain of LBV-AD patients, we used valproic acid (VPA) to increase its endogenous expression levels. The release of α-Syn from damaged presynaptic terminals that occurs during the course of the disease was simulated by challenging cells with recombinant α-Syn. Our results showed that either VPA-induced α-Syn upregulation or addition of recombinant α-Syn protect primary cortical neurons from soluble Aß1-42 decreasing the caspase-3-mediated cell death. It was also found that neuroprotection against Aß-induced toxicity mediated by α-Syn overexpression involves the PI3K/Akt cell survival pathway. Furthermore, recombinant α-Syn was shown to directly interact with Aß1-42 and to decrease the levels of Aß1-42 oligomers, which might explain its neuroprotective effect. In conclusion, we demonstrate that either endogenous or exogenous α-Syn can be neuroprotective against Aß-induced cell death, suggesting a cell defence mechanism during the initial stages of the mixed pathology.


Subject(s)
Alzheimer Disease/physiopathology , Amyloid beta-Peptides/toxicity , Neurons/drug effects , Peptide Fragments/toxicity , alpha-Synuclein/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Caspase 3/metabolism , Cerebral Cortex/cytology , Neurons/metabolism , Peptide Fragments/metabolism , Rats , Valproic Acid/pharmacology , alpha-Synuclein/metabolism
4.
Prog Neuropsychopharmacol Biol Psychiatry ; 35(2): 348-55, 2011 Mar 30.
Article in English | MEDLINE | ID: mdl-20736041

ABSTRACT

Several diseases are known to have a multifactorial origin, depending not only on genetic but also on environmental factors. They are called "complex disorders" and include cardiovascular disease, cancer, diabetes, and neuropsychiatric and neurodegenerative diseases. In the latter class, Alzheimer's (AD) and Parkinson's diseases (PD) are by far the most common in the elderly and constitute a tremendous social and economical problem. Both disorders present familial and sporadic forms and although some polymorphisms and risk factors have been associated with AD and PD, the precise way by which the environment contributes to neurodegeneration is still unclear. Recent studies suggest that environmental factors may contribute for neurodegeneration through induction of epigenetic modifications, such as DNA methylation, and chromatin remodeling, which may induce alterations in gene expression programs. Epigenetics, which refers to any process that alters gene activity without changing the actual DNA sequence, and leads to modifications that can be transmitted to daughter cells, is a relatively novel area of research that is currently attracting a high level of interest. Epigenetic modulation is present since the prenatal stages, and the aging process is now accepted to be associated with a loss of phenotypic plasticity to epigenetic modifications. Since aging is the most important risk factor for idiopathic AD and PD, it is expected that epigenetic alterations on DNA and/or chromatin structure may also accumulate in neurodegeneration, accounting at least in part to the etiology of these disorders.


Subject(s)
Aging , Alzheimer Disease/genetics , Epigenesis, Genetic , Nerve Degeneration/genetics , Neurodegenerative Diseases/genetics , Parkinson Disease/genetics , Aging/genetics , Aging/pathology , Aging/physiology , Alzheimer Disease/complications , Alzheimer Disease/etiology , Alzheimer Disease/pathology , Humans , Inheritance Patterns , Nerve Degeneration/complications , Nerve Degeneration/etiology , Nerve Degeneration/pathology , Neurodegenerative Diseases/complications , Neurodegenerative Diseases/etiology , Parkinson Disease/complications , Parkinson Disease/etiology , Parkinson Disease/pathology , Polymorphism, Genetic , Risk Factors
5.
J Alzheimers Dis ; 21(2): 373-83, 2010.
Article in English | MEDLINE | ID: mdl-20555132

ABSTRACT

Alzheimer's disease (AD) is a complex disorder of the central nervous system that affects an increasing number of people worldwide due to the overall aging of the human population. In addition to genetics, which accounts for a small fraction of all cases, the etiology is multifactorial with other currently unknown triggers. It is crucial to unravel the physiological mechanisms that, being disrupted, could lead to neurodegeneration, as this knowledge could ultimately lead to the identification of novel neuroprotective strategies that could be used as therapeutics. Although mitochondrial dysfunction and the resultant oxidative stress are believed to play a major role in the pathogenesis of both early- and late-onset AD, it is conceivable that the altered physiological state of the cells leading to sporadic AD could involve additional mechanisms. Much evidence suggests that epigenetic modification of gene expression can accumulate with age leading to an altered response to stress and to an enhanced susceptibility to diseases. Since aging has a major impact in different late-onset, complex diseases and, in particular, in the late-onset forms of AD, epigenetic alterations might play an important role in the pathophysiology of this disorder. Studies exploring this idea are underway and suggest that both methylation abnormalities in AD-related genes due to disruption of mechanisms that regulate the availability of methyl groups (SAM/HCY cycle) and changes of global histone acetylation levels might play a role in neurodegeneration. Thus, it is essential to undertake novel global approaches, which may lead to the development of new avenues for therapeutic intervention.


Subject(s)
Alzheimer Disease , DNA Methylation/physiology , Epigenesis, Genetic/physiology , Nerve Degeneration , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Humans , Nerve Degeneration/genetics , Nerve Degeneration/metabolism , Nerve Degeneration/physiopathology
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