SCA8 mRNA expression suggests an antisense regulation of KLHL1 and correlates to SCA8 pathology

Chen, Wei Lun; Lin, Jian; Huang, Hei Jen; Wang, Su Min; Su, Ming; Lee-Chen, Guey Jen; Chen, Chiung Mei; Hsieh-Li, Hsiu Mei

doi:10.1016/j.brainres.2008.07.096

Cited by 40 publications

(24 citation statements)

References 35 publications

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“…Klhl1 is primarily expressed in the brain (Chen et al, 2008), and we showed for the first time that the expression pattern of Klhl1 strongly resembles that of Nurr1 in the mdDA area and other Nurr1-positive structures. Klhl1 is the homolog of the actin-organizing kelch gene in…”

Section: The Role Of Klhl1 In Mdda Neuronsmentioning

confidence: 88%

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

et al. 2009

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The orphan nuclear receptor Nurr1 is essential for the development of meso-diencephalic dopamine (mdDA) neurons and is required, together with the homeobox transcription factor Pitx3, for the expression of genes involved in dopamine metabolism. In order to elucidate the molecular mechanisms that underlie the neuronal deficits in Nurr1 -/-mice, we performed combined gene expression microarrays and ChIP-on-chip analysis and thereby identified Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in vivo. In line with the previously described cooperativity between Nurr1 and Pitx3, we show that the expression of Ptpru and Klhl1 in mdDA neurons is also dependent on Pitx3. Furthermore, we demonstrate that Nurr1 interacts with the Ptpru promoter directly and requires Pitx3 for full expression of Ptpru in mdDA neurons. By contrast, the expression of Dlk1 is maintained in Pitx3 -/-embryos and is even expanded into the rostral part of the mdDA area, suggesting a unique position of Dlk1 in the Nurr1 and Pitx3 transcriptional cascades. Expression analysis in Dlk1 -/-embryos reveals that Dlk1 is required to prevent premature expression of Dat in mdDA neuronal precursors as part of the multifaceted process of mdDA neuronal differentiation driven by Nurr1 and Pitx3. Taken together, the involvement of Nurr1 and Pitx3 in the expression of novel target genes involved in important neuronal processes such as neuronal patterning, axon outgrowth and terminal differentiation, opens up new avenues to study the properties of mdDA neurons during development and in neuronal pathology as observed in Parkinson's disease.

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Section: The Role Of Klhl1 In Mdda Neuronsmentioning

confidence: 88%

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

et al. 2009

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“…Recent studies have revealed that surprisingly large numbers of human genes are associated with antisense transcripts (31). Moreover, antisense transcription has been reported in five TNR disease genes (5,6,9,35,49), and at least 10 other TNR disease genes are represented in the antisense transcriptomes of several human cell lines (27). These observations suggest that simultaneous sense and antisense transcription-which we define as convergent transcription-occur in an unexpectedly high fraction of the human genome, including genes associated with TNR diseases.…”

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confidence: 88%

“…Antisense transcription occurs in a high fraction of the genes in the human genome (31), including most of the genes in which expansions of repeat sequences cause disease (5,6,27,35,49). These studies led us to test the effects of antisense transcription on triplet repeats in human cells.…”

Section: Discussionmentioning

confidence: 99%

Convergent Transcription through a Long CAG Tract Destabilizes Repeats and Induces Apoptosis

Lin

Leng

Wan

et al. 2010

Molecular and Cellular Biology

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Short repetitive sequences are common in the human genome, and many fall within transcription units. We have previously shown that transcription through CAG repeat tracts destabilizes them in a way that depends on transcription-coupled nucleotide excision repair and mismatch repair. Recent observations that antisense transcription accompanies sense transcription in many human genes led us to test the effects of antisense transcription on triplet repeat instability in human cells. Here, we report that simultaneous sense and antisense transcription (convergent transcription) initiated from two inducible promoters flanking a CAG 95 tract in a nonessential gene enhances repeat instability synergistically, arrests the cell cycle, and causes massive cell death via apoptosis. Using chemical inhibitors and small interfering RNA (siRNA) knockdowns, we identified the ATR (ataxia-telangiectasia mutated [ATM] and Rad3 related) signaling pathway as a key mediator of this cellular response. RNA polymerase II, replication protein A (RPA), and components of the ATR signaling pathway accumulate at convergently transcribed repeat tracts, accompanied by phosphorylation of ATR, CHK1, and p53. Cell death depends on simultaneous sense and antisense transcription and is proportional to their relative levels, it requires the presence of the repeat tract, and it occurs in both proliferating and nonproliferating cells. Convergent transcription through a CAG repeat represents a novel mechanism for triggering a cellular stress response, one that is initiated by events at a single locus in the genome and resembles the response to DNA damage.

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“…These can be generated by processing longer double-stranded RNAs formed by complementary pairing of mRNAs and long antisense transcripts due to bidirectional transcription at the same locus [Morris, 2009]. The presence of long ncRNAs overlapping (at least in part) critical mRNAs has been proven in several imprinted loci such as those of Angelman and Beckwith-Wiedemann syndromes [Rougeulle et al, 1998;Lee et al, 1999] as well as those of Fragile X [Ladd et al, 2007;Chen et al, 2008;De Biase et al, 2009]. It is assumed that double-stranded RNAs are processed by the RNAi machinery into siRNAs that induce either degradation of complementary mRNAs (post-transcriptional gene silencing) or cause RNA-mediated DNA methylation (transcriptional gene silencing).…”

Section: Rna Transcriptsmentioning

confidence: 99%

Epigenetics, fragile X syndrome and transcriptional therapy

Tabolacci

Chiurazzi

2013

American J of Med Genetics Pt A

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Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic mechanisms therefore include all transcriptional controls that determine how genes are expressed during development and differentiation, but also in individual cells responding to environmental stimuli. The purpose of this review is to examine the basic principles of epigenetic mechanisms and their contribution to human disorders with a particular focus on fragile X syndrome (FXS), the most common monogenic form of developmental cognitive impairment. FXS represents a prototype of the so-called repeat expansion disorders due to "dynamic" mutations, namely the expansion (known as "full mutation") of a CGG repeat in the 5 0 UTR of the FMR1 gene. This genetic anomaly is accompanied by epigenetic modifications (mainly DNA methylation and histone deacetylation), resulting in the inactivation of the FMR1 gene. The presence of an intact FMR1 coding sequence allowed pharmacological reactivation of gene transcription, particularly through the use of the DNA demethylating agent 5 0 -aza-2 0 -deoxycytydine and/or inhibitors of histone deacetylases. These treatments suggested that DNA methylation is dominant over histone acetylation in silencing the FMR1 gene. The importance of DNA methylation in repressing FMR1 transcription is confirmed by the existence of rare unaffected males carrying unmethylated full mutations. Finally, we address the potential use of epigenetic approaches to targeted treatment of other genetic conditions. Ó 2013 Wiley Periodicals, Inc.Key words: fragile X syndrome; epigenetics; transcriptional therapy INTRODUCTION When in 1942 Conrad H. Waddington coined the term "epigenetics," the exact nature of genes and their role in heredity and in transcriptional regulation was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype [Waddington, 1942]. The term is a portmanteau of the words epigenesis (differentiation of cells from their initial totipotent state in embryonic development) and genetics. Only in 2008 at a Cold Spring harbor meeting, consensus was reached on the definition of epigenetic trait, as "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" [Berger et al., 2009]. The greek prefix epi-refers to features that are "on top of" genetics, that is, all those stable but reversible changes to DNA, RNA and proteins that regulate gene expression and allow cells with the same DNA to do different things at different times.Broadly speaking, epigenetic mechanisms include all transcriptional controls that regulate gene expression, whether during development and differentiation or in mature cells responding to the environment. Epigenetic changes can be inherited (e.g., imprinting) and be relatively stable (e.g., chromosome X inactivation), but are often rapidly imposed or removed on a given locus according to cell needs. Four major layers of epigenetic controls have ...

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SCA8 mRNA expression suggests an antisense regulation of KLHL1 and correlates to SCA8 pathology

Cited by 40 publications

References 35 publications

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

Convergent Transcription through a Long CAG Tract Destabilizes Repeats and Induces Apoptosis

Epigenetics, fragile X syndrome and transcriptional therapy

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