Transcriptional dysregulation of coding and non ... - Semantic Scholar

1270

Biochemical Society Transactions (2009) Volume 37, part 6

Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington’s disease Angela Bithell*1 , Rory Johnson† and Noel J. Buckley* *Department of Neuroscience, Institute of Psychiatry, King’s College London, CCBB, London SE5 9JU, U.K. and †Genome Institute of Singapore, 60 Biopolis Street, No. 02-01, Genome Building, 138672, Singapore

Abstract HD (Huntington’s disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

Introduction The Htt (Huntingtin) gene was first identified in 1993 by the efforts of the Huntington’s Disease Collaborative Research Group, where an abnormally long and unstable CAG repeat (CAG)n was identified in HD (Huntington’s disease) patients [1]. Of those HD patients, most had between (CAG)42 and (CAG)66 compared with less than (CAG)35 in unaffected populations (some HD individuals had many more than 66 repeats). The expanded CAG repeats lead to an elongated glutamine tract [polyQ (polyglutamine)] in the N-terminus of the Htt protein. Expansion of trinucleotide repeat sequences such as (CAG)n was already known in several other genetic disorders including an expanded CTG repeat in myotonic dystrophy and CGG repeat in fragile X syndrome. However, sequence analysis of the large 348 kDa ubiquitously expressed Htt protein gave few clues to its function since it had little

Key words: brain-derived neurotrophic factor (BDNF), Huntingtin, Huntington’s disease (HD), microRNA (miRNA), neuronal dysfunction, repressor element 1-silencing transcription factor (REST). Abbreviations used: BDNF, brain-derived neurotrophic factor; ChIP, chromatin immunoprecipitation; GOF, gain-of-function; HD, Huntington’s disease; HDAC, histone deacetylase; Htt, Huntingtin; LOF, loss-of-function; miRNA, microRNA; mutHtt, mutant Htt; polyQ, polyglutamine; RE1, repressor element 1; REST, RE1-silencing transcription factor. 1 To whom correspondence should be addressed (email [email protected]).

 C The

C 2009 Biochemical Society Authors Journal compilation 

homology to any known proteins. However, though our current understanding of its functions is far from complete, the work of several groups has begun to identify the role of both Htt and mutHtt (mutant Htt). Since HD is a dominant disorder, it is predicted that the mutHtt results in a GOF (gain-of-function) mechanism that ultimately results in neuronal death. Indeed there is a body of evidence for a conversion of Htt from neuroprotective to neurotoxic in HD [2]. By way of example, there is an inverse correlation between age of onset in HD and length of the polyQ tract whereby more CAG repeats are associated with an earlier disease onset, suggesting that mutHtt toxicity underlies disease pathology [3,4]. However, in addition to this GOF for mutHtt, it is likely that LOF (loss-of-function) of wild-type Htt also contributes to HD. In particular, evidence from both HD patients and animal models of HD show widespread changes in gene expression in neuronal [5–11] and non-neuronal cells [10,12]. Here, disruption to the normal interaction of Htt with factors that control gene expression might affect cell survival or functionality, as has been suggested for BDNF (brain-derived neurotrophic factor) [10,13,14]. Htt is known to interact with a number of transcriptional regulators including Sp1 (specificity protein 1) and TAFII130 Biochem. Soc. Trans. (2009) 37, 1270–1275; doi:10.1042/BST0371270

Gene Expression in Neuronal Disease

(TATA-box-binding protein-associated factor II, 130 kDa) [15,16], CREB (cAMP-response-element-binding protein) and p53 [17] and REST [RE1 (repressor element 1)-silencing transcription factor]/NRSF (neuron-restrictive silencing factor) [13]. The interaction of Htt with the last of these transcriptional regulators, REST, constitutes an intriguing mechanism of gene regulation which, when disrupted in HD, could explain many of the underlying causes of neuronal dysfunction. Work by several groups including our own has revealed changes in the expression of many genes associated with HD that are direct targets of REST repression. More recently, a number of studies have shown dysregulation of gene expression in HD by changes to miRNA (microRNA) expression, thus additionally affecting post-transcriptional gene regulation [18,19]. Again, many of these miRNAs are REST targets, adding a second layer of complexity to Htt/REST-mediated control of neuronal gene expression subsequently affected in HD [18,20]. In this review, we will briefly discuss the role of REST and Htt in HD, including dysregulation of REST targets (both coding and non-coding), the interaction between REST and Htt, and how the presence of mutHtt and the consequent aberrant interactions of REST with its target genes might result in changes to the neuronal transcriptome that contribute to HD pathology.

REST REST is a transcriptional repressor that acts as a master regulator of neuronal genes in both neural [21,22] and nonneural cells [23] and to a lesser extent regulates non-neuronal genes [10,24] often in a highly cell-context-dependent manner [25]. In addition, despite its most well-known role in repressing neuronal genes in non-neuronal cells, REST mRNA expression is retained in populations of mature neurons. REST protein is comprised of a zinc-finger DNAbinding domain and N- and C-terminal repressor domains (Figure 1) that are important for its repressor functions (see [26] for review). REST is recruited via its DNA-binding domain to a 21 bp cis-regulatory motif known as the RE1 [27,28]. It should be noted, however, that this represents the canonical RE1 element and subsequent genome-wide ChIP (chromatin immunoprecipitation) experiments have revealed non-canonical binding sites, most commonly those with alternative spacers [24]. The N-terminal domain of REST then serves to recruit the co-repressor Sin3A together with HDACs (histone deacetylases) such as HDAC1 and HDAC2 able to repress gene expression by removal of acetyl groups on core histones including Lys9 of histone H3 (H3K9Ac) (Figure 1). Meanwhile, the C-terminal domain can recruit a variety of factors including CoREST, the histone demethylase LSD1 (removes methyl groups from monoand di-methylated H3K4), the histone methyltransferase G9a (methylates H3K9) and chromatin remodelling factors such as BAF170, BRAF35 and BRG1; together these factors lead to transcriptional repression [29–31]. The particular combination of co-factors recruited by REST is dependent on

Figure 1 Interaction of REST with transcriptional regulators at RE1s REST binds to RE1 sites in the genome and exerts its repressive function by its interaction with a variety of co-regulator proteins. Shown are examples of REST co-regulators including: co-repressor Sin3a; CoREST; histone modifying enzymes such as HDACs, the histone methyltransferase G9a and the histone demethylase LSD1; chromatin remodelling enzymes BAF170, BRG1, BAF57 and BRAF35; and the methyl CpG-binding protein, MeCP2.

the target locus as well as cell-type, thereby allowing contextspecific REST effects. Studies by a number of groups including our own have used a variety of methodologies to identify REST target genes, giving us a comprehensive knowledge of RE1-containing genes in both the mouse and human genomes, with many experimentally validated to show recruitment of REST in particular cellular contexts [24,32–36]. In particular, the large, conserved RE1 has greatly facilitated bioinformatics approaches to REST target discovery; a task impossible for the vast majority of transcription factors whose known DNA-binding motifs are too short and thus too numerous in the genome for this type of approach [35,37]. At present, there are as many as 2000 putative REST targets based on RE1 sequences (both canonical and non-canonical) or REST occupancy (adjudged by ChIP). Furthermore, many RE1s are found in genes important for neuronal function, including synaptic transmission, and many of these target genes are dysregulated either in HD patients or in mouse models of HD, including Bdnf . Thus, REST has the potential to regulate large cohorts of genes when recruited to these loci, although only a subset of these predicted targets are functionally repressed in any given cell-type.

Htt, REST and BDNF expression The medium spiny striatal neurons that are preferentially lost in HD require trophic support in the form of BDNF that is made by cortical neurons and transported to the striatum via cortico-striatal afferents [38]. In 2001, using mouse models of HD, Zuccato et al. [13] showed that Htt positively regulates expression of the BDNF gene via the Bdnf promoter II while mutHtt led to reduced levels of BDNF. They subsequently  C The

C 2009 Biochemical Society Authors Journal compilation 

1271

1272

Biochemical Society Transactions (2009) Volume 37, part 6

Figure 2 Disruption to the REST–Htt interaction in HD Wild-type Htt sequesters REST in the cytoplasm, preventing binding of REST to the RE1 in the Bdnf promoter (A). Aberrant interaction of mutHtt carrying an expanded polyQ tract with REST leads to REST translocating to the nucleus where it binds the RE1 in the Bdnf promoter and represses its transcription (B). Abbreviations: Bdnf, brain-derived neurotrophic factor.

showed that wild-type Htt in neural cells sequesters REST in the cytoplasm, preventing REST repression of BDNF via recruitment to an RE1 in the Bdnf promoter II [14] (Figure 2A). Importantly, the presence of mutHtt leads to reduced interaction between mutHtt and REST, nuclear levels of REST subsequently increase and levels of BDNF correspondingly decrease (Figure 2B). Later evidence from a second group showed that Htt in fact interacts with REST indirectly in a complex containing dynactin p150glued , RILP (REST-interacting LIM domain protein) and REST [39]. Furthermore, in neuronal cells the addition of HAP1 (Httassociated protein 1) to this complex acts to retain REST in the cytoplasm [39]. These data have revealed an intriguing mechanism by which loss of normal Htt function can lead to aberrant RESTmediated repression of BDNF expression in neurons that subsequently leads to a loss of trophic support, leaving striatal neurons vulnerable in HD [38]. However, as discussed above, REST has a large number of neuronal target genes thus raising the question of whether elevated levels of nuclear REST in neuronal cells in HD has a more widespread effect on the neuronal transcriptome.

Widespread REST-mediated gene dysregulation in HD The 2003 study of Zuccato et al. [14] provided the first evidence that there was indeed a more global role for this Htt/REST mechanism of neuronal gene regulation in HD. In addition to decreased levels of BDNF, they reported decreased mRNA levels of other RE1-containing genes in the presence of mutHtt whose levels were increased following overexpression of wild-type Htt; these genes included synapsin 1 (Syn1) and cholinergic receptor nicotinic beta polypeptide 2 (Chrnb2) [14]. Importantly, these two genes also showed reduced expression in HD post-mortem samples [14]. This was followed up by a comprehensive study using ChIP analyses to detect REST occupancy at RE1 targets in both HD cell models, mouse models of HD and in human post-mortem HD samples from the parietal  C The

C 2009 Biochemical Society Authors Journal compilation 

cortex [10]. Increased REST occupancy of large numbers of RE1-containing genes is associated with HD and leads to a down-regulation of gene transcription. Strikingly, this increased REST-mediated repression of target genes also occurs in mice depleted of normal Htt in the absence of mutHtt and is dose-dependent [10]. Thus LOF mechanisms are likely to contribute to HD pathology together with GOF brought about by toxic effects of mutHtt, and mutHtt itself may reduce wild-type Htt levels by sequestration into aggregates [40]. Furthermore, many genes identified from ChIP approaches reveal REST recruitment to a number of genes that may be particularly relevant in the context of other known defects in the HD brain; these include the ornithine aminotransferase mitochondrial precursor gene (OAT) whose role in glutamate synthesis was suggested to correlate with known deficits in the glutamatergic pathway in mouse HD models [10,41]. Although HD pathology is often viewed predominantly as affecting populations of neuronal cells, it is of note that nonneuronal populations, both within the nervous system and in non-neural tissues, are also affected. Intriguingly, astrocytes, which greatly outnumber neurons in the adult brain, have been shown to have reduced glutamate transporters in mouse models of HD that could lead to increased neuronal excitotoxicity [42] and it would be interesting to examine any potential role of REST in regulating this process. Outside of the nervous system, there is evidence that increased REST occupancy may underlie some of the non-neuronal defects observed such as those in spermatogenesis in Hdh−/− mice [43]. In this case, ‘ChIP–chip’ analysis was used to demonstrate that the Ddx25 gene encoding an ATPdependent RNA helicase essential for spermatid development had increased REST occupancy in human HD samples [10]. So far, it is clear that there are widespread changes to gene expression in HD, particularly to the neuronal transcriptome and that this is due, at least in part, to a loss of Httmediated control of transcription [44]. Moreover, growing evidence supports a key role for REST in this regulation whereby Htt indirectly sequesters REST in the cytoplasm to prevent its repression of RE1-regulated genes whose functions control diverse aspects of neuronal development, function and survival [10,14]. mutHtt is unable to interact with REST to prevent its nuclear localization, resulting in a global repression of genes critical for neuronal cells including BDNF, a neurotrophic factor implicated in a number of neurodegenerative disorders [45]. However, more recently the proposed disruption to transcriptional regulation in HD has been expanded to include altered expression of ncRNAs (non-coding RNAs) [18,19]. These include miRNAs that provide post-transcriptional control of gene expression and again REST is a strong candidate as a mediator of altered miRNA expression via loss of Htt/REST interaction.

miRNA targets of REST in HD miRNAs are produced by a complex synthesis pathway that ultimately results in short, approx. 21 nt, RNAs that

Gene Expression in Neuronal Disease

associate with the RISC (RNA-induced silencing complex) and lead to silencing of specific target mRNA either via inhibition of translation or degradation of the mRNA [46]. miRNAs show tissue-specific expression and function and a considerable number are specifically expressed in the developing or adult brain [46,47]. An example is mir-9, an miRNA regulated during embryonic brain development, involved in neuronal/glial differentiation of embryonic stem cells and down-regulated in PS1 (presenilin 1)-knockout mice [48,49]. More critically from the perspective of neurodegenerative disorders, miRNAs are increasingly being assigned neuroprotective roles and thus when dysregulated may contribute to disease pathology [20]. Many such reports also describe roles not just in neurodegenerative disorders but more specifically in those involving polyQ-mediated pathogenicity [50,51]. Recent analyses have shown post-transcriptional regulation of gene expression by miRNAs to be disrupted in HD [18,19]. Earlier in 2006, studies had already shown REST to regulate a number of miRNAs in both mouse [52] and human [53] and, perhaps not surprisingly, a large number of miRNAs with aberrant expression in HD were found to be REST targets, including mir-9, mir-9* and mir-124 [18–20]. Having identified a number of putative REST miRNA targets by mapping computationally predicted REST-binding sites to annotated miRNAs, Johnson et al. [18] showed that several miRNAs were regulated by REST repressor activity in mouse neural cells including mir-29a, mir-132 and mir-135b. These same three miRNAs showed decreased expression in the cerebral cortex of the R6/2 HD mouse model [transgenic for Htt exon 1 with a (CAG)145 ] [54] as did mir-124 whose downstream targets were correspondingly up-regulated [18] and whose regulation by REST is supported by evidence from other studies [19,52,53]. mir-124 is of particular interest since it is responsible for preventing expression of nonneuronal genes in neuronal cells (post-transcriptionally) in obverse contrast to REST’s role in repression of neuronal genes (in non-neuronal cells) [52]. Thus, in HD, inappropriate repression of mir-124 due to increased nuclear REST results in a decrease in mir-124 and a consequent increase in expression of mir-124 targets (Figure 3), ultimately leading to neuronal cells losing aspects of their neuronal identity [55]. Intriguingly, Johnson et al. [18,20], also describe brain regionspecific changes in dysregulation of miRNA expression in HD, which is highlighted as one potential explanation for the distinctive neuron-specific loss that is such a characteristic feature of HD. A bioinformatics exploration of previously published microarray data from the caudate of HD patients [8] has also further illustrated the relationship between targets of REST or mir-124 and the widespread gene expression changes observed in human HD patients [20]. This analysis tested the hypothesis that if REST plays a key role in the dysregulation of large cohorts of genes in HD, genes with an associated RE1 will be enriched in a down-regulated gene-set from HD patients. Concomitantly, targets of mir-124 (itself a target for REST repression), will encounter derepression due

Figure 3 Model of REST-mediated gene dysregulation in HD REST has both coding and non-coding gene targets including Bdnf and mir-124/mir-132 respectively. BDNF promotes neuronal survival, while mir-124 and mir-132 post-transcriptionally repress non-neuronal genes or genes involved in inhibition of neuronal function. BDNF also positively regulates mir-124. The Figure shows the model in wild-type cells (top panel) and cells with mutHtt (bottom panel). Wild-type Htt (WT Htt) sequesters REST in the cytoplasm, allowing REST targets to be expressed. mutHtt leads to increased nuclear levels of REST protein and subsequent repression of Bdnf, mir-124 and mir-132. Consequently, there is a loss of BDNF (and decreased neuronal survival) and mir-124 and mir-132 targets are derepressed, including the REST co-factor CTDSP1 and p250GAP respectively. Levels of expression/activity are represented by colour, with light grey indicating lower levels and black indicating higher levels.

to loss of mir-124 and thus should be enriched in those genes up-regulated in HD. In both cases, the results were consistent with the hypothesis: REST targets are significantly enriched in the down-regulated gene fraction and mir124 targets are significantly enriched in the up-regulated fraction. Despite acknowledged methodological limitations, this type of analysis lends additional credence to the notion of a major role of the Htt/REST transcriptional dysregulation in HD pathology.

Summary HD is a dominantly inherited, incurable neurodegenerative disease caused by an expanded polyQ tract in the Htt protein. Despite evidence for neurotoxicity elicited by mutHtt replacing the neuroprotection offered by Htt, the widespread dysregulation of gene expression associated with HD has also been attributed to the loss of normal transcriptional regulation controlled by Htt interaction with a variety of transcriptional regulator proteins. One of these regulators is REST, whose major role is that of a master regulator of neuronal genes, repressing their expression in both nonneuronal and neuronal cells. Neuronal REST is largely sequestered together with Htt in the cytoplasm, but, in the  C The

C 2009 Biochemical Society Authors Journal compilation 

1273

1274

Biochemical Society Transactions (2009) Volume 37, part 6

presence of mutHtt, this complex is disrupted and REST migrates to the nucleus, ultimately resulting in aberrant repression of its target genes. In addition to a direct repression of REST target genes, the increase in nuclear REST results in repression of miRNAs and a subsequent increase in miRNA target genes expression. Thus, REST has a bimodal function in the dysregulation of gene expression in HD, resulting in a direct decrease and an indirect increase in expression of distinct cohorts of genes. By increasing our understanding of the underlying mechanisms that govern transcriptional dysregulation in HD, we also open up potential avenues for therapeutic intervention by restoration of affected downstream gene function. Further studies to explore the other transcriptional pathways controlled by Htt together with those described here for REST will prove an invaluable resource in the HD field.

Acknowledgement We apologize for the omission of many important references due to the limitations of space within this review.

Funding This work is supported by the Wellcome Trust and Agency for Science and Technology Research (Singapore).

References 1 The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983 2 Cattaneo, E., Zuccato, C. and Tartari, M. (2005) Normal Huntingtin function: an alternative approach to Huntington’s disease. Nat. Rev. Neurosci. 6, 919–930 3 Andrew, S.E., Goldberg, Y.P., Kremer, B., Telenius, H., Theilmann, J., Adam, S., Starr, E., Squitieri, F., Lin, B., Kalchman, M.A. et al. (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat. Genet. 4, 398–403 4 Snell, R.G., MacMillan, J.C., Cheadle, J.P., Fenton, I., Lazarou, L.P., Davies, P., MacDonald, M.E., Gusella, J.F., Harper, P.S. and Shaw, D.J. (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease. Nat. Genet. 4, 393–397 5 Augood, S.J., Faull, R.L. and Emson, P.C. (1997) Dopamine D1 and D2 receptor gene expression in the striatum in Huntington’s disease. Ann. Neurol. 42, 215–221 6 Luthi-Carter, R., Strand, A., Peters, N.L., Solano, S.M., Hollingsworth, Z.R., Menon, A.S., Frey, A.S., Spektor, B.S., Penney, E.B., Schilling, G. et al. (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum. Mol. Genet. 9, 1259–1271 7 Luthi-Carter, R., Strand, A.D., Hanson, S.A., Kooperberg, C., Schilling, G., La Spada, A.R., Merry, D.E., Young, A.B., Ross, C.A., Borchelt, D.R. and Olson, J.M. (2002) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington’s disease mouse models reveal context-independent effects. Hum. Mol. Genet. 11, 1927–1937 8 Hodges, A., Strand, A.D., Aragaki, A.K., Kuhn, A., Sengstag, T., Hughes, G., Elliston, L.A., Hartog, C., Goldstein, D.R., Thu, D. et al. (2006) Regional and cellular gene expression changes in human Huntington’s disease brain. Hum. Mol. Genet. 15, 965–977 9 Kuhn, A., Goldstein, D.R., Hodges, A., Strand, A.D., Sengstag, T., Kooperberg, C., Becanovic, K., Pouladi, M.A., Sathasivam, K., Cha, J.H. et al. (2007) Mutant Huntingtin’s effects on striatal gene expression in mice recapitulate changes observed in human Huntington’s disease brain and do not differ with mutant Huntingtin length or wild-type Huntingtin dosage. Hum. Mol. Genet. 16, 1845–1861  C The

C 2009 Biochemical Society Authors Journal compilation 

10 Zuccato, C., Belyaev, N., Conforti, P., Ooi, L., Tartari, M., Papadimou, E., MacDonald, M., Fossale, E., Zeitlin, S., Buckley, N. and Cattaneo, E. (2007) Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington’s disease. J. Neurosci. 27, 6972–6983 11 Benn, C.L., Sun, T., Sadri-Vakili, G., McFarland, K.N., DiRocco, D.P., Yohrling, G.J., Clark, T.W., Bouzou, B. and Cha, J.H. (2008) Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J. Neurosci. 28, 10720–10733 12 Marullo, M., Valenza, M., Mariotti, C., Di Donato, S., Cattaneo, E. and Zuccato, C. (2008) Analysis of the repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy of non-neuronal genes in peripheral lymphocytes from patients with Huntington’s disease. Brain Pathol., doi:10.1111/j.1750-3639.2008.00249.x 13 Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B.R., Goffredo, D., Conti, L., MacDonald, M.E., Friedlander, R.M., Silani, V., Hayden, M.R. et al. (2001) Loss of Huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293, 493–498 14 Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B.R., Hayden, M.R., Timmusk, T. et al. (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat. Genet. 35, 76–83 15 Dunah, A.W., Jeong, H., Griffin, A., Kim, Y.M., Standaert, D.G., Hersch, S.M., Mouradian, M.M., Young, A.B., Tanese, N. and Krainc, D. (2002) Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 296, 2238–2243 16 Qiu, Z., Norflus, F., Singh, B., Swindell, M.K., Buzescu, R., Bejarano, M., Chopra, R., Zucker, B., Benn, C.L., DiRocco, D.P. et al. (2006) Sp1 is up-regulated in cellular and transgenic models of Huntington disease, and its reduction is neuroprotective. J. Biol. Chem. 281, 16672–16680 17 Steffan, J.S., Kazantsev, A., Spasic-Boskovic, O., Greenwald, M., Zhu, Y.Z., Gohler, H., Wanker, E.E., Bates, G.P., Housman, D.E. and Thompson, L.M. (2000) The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. U.S.A. 97, 6763–6768 18 Johnson, R., Zuccato, C., Belyaev, N.D., Guest, D.J., Cattaneo, E. and Buckley, N.J. (2008) A microRNA-based gene dysregulation pathway in Huntington’s disease. Neurobiol. Dis. 29, 438–445 19 Packer, A.N., Xing, Y., Harper, S.Q., Jones, L. and Davidson, B.L. (2008) The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington’s disease. J. Neurosci. 28, 14341–14346 20 Johnson, R. and Buckley, N.J. (2009) Gene dysregulation in Huntington’s disease: REST, microRNAs and beyond. Neuromol. Med. 11, 183–199 21 Palm, K., Belluardo, N., Metsis, M. and Timmusk, T. (1998) Neuronal expression of zinc finger transcription factor REST/NRSF/XBR gene. J. Neurosci. 18, 1280–1296 22 Wood, I.C., Belyaev, N.D., Bruce, A.W., Jones, C., Mistry, M., Roopra, A. and Buckley, N.J. (2003) Interaction of the repressor element 1-silencing transcription factor (REST) with target genes. J. Mol. Biol. 334, 863–874 23 Belyaev, N.D., Wood, I.C., Bruce, A.W., Street, M., Trinh, J.B. and Buckley, N.J. (2004) Distinct RE-1 silencing transcription factor-containing complexes interact with different target genes. J. Biol. Chem. 279, 556–561 24 Johnson, R., Teh, C.H., Kunarso, G., Wong, K.Y., Srinivasan, G., Cooper, M.L., Volta, M., Chan, S.S., Lipovich, L., Pollard, S.M. et al. (2008) REST regulates distinct transcriptional networks in embryonic and neural stem cells. PLoS Biol. 6, e256 25 Hermanson, O. (2008) Stem cells have different needs for REST. PLoS Biol. 6, e271 26 Ooi, L. and Wood, I.C. (2007) Chromatin crosstalk in development and disease: lessons from REST. Nat. Rev. Genet. 8, 544–554 27 Chong, J.A., Tapia-Ramirez, J., Kim, S., Toledo-Arai, J.J., Zheng, Y., Boutros, M.C., Altshuller, Y.M., Frohman, M.A., Kraner, S.D. and Mandel, G. (1995) REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80, 949–957 28 Schoenherr, C.J. and Anderson, D.J. (1995) The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267, 1360–1363 29 Bernstein, B.E., Meissner, A. and Lander, E.S. (2007) The mammalian epigenome. Cell 128, 669–681

Gene Expression in Neuronal Disease

30 Nightingale, K.P., O’Neill, L.P. and Turner, B.M. (2006) Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. Curr. Opin. Genet. Dev. 16, 125–136 31 Zheng, D., Zhao, K. and Mehler, M.F. (2009) Profiling RE1/REST-mediated histone modifications in the human genome. Genome Biol. 10, R9 32 Schoenherr, C.J., Paquette, A.J. and Anderson, D.J. (1996) Identification of potential target genes for the neuron-restrictive silencer factor. Proc. Natl. Acad. Sci. U.S.A. 93, 9881–9886 33 Bruce, A.W., Donaldson, I.J., Wood, I.C., Yerbury, S.A., Sadowski, M.I., Chapman, M., Gottgens, B. and Buckley, N.J. (2004) Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proc. Natl. Acad. Sci. U.S.A. 101, 10458–10463 34 Bruce, A.W., Lopez-Contreras, A.J., Flicek, P., Down, T.A., Dhami, P., Dillon, S.C., Koch, C.M., Langford, C.F., Dunham, I., Andrews, R.M. and Vetrie, D. (2009) Functional diversity for REST (NRSF) is defined by in vivo binding affinity hierarchies at the DNA sequence level. Genome Res. 19, 994–1005 35 Mortazavi, A., Leeper Thompson, E.C., Garcia, S.T., Myers, R.M. and Wold, B. (2006) Comparative genomics modeling of the NRSF/REST repressor network: from single conserved sites to genome-wide repertoire. Genome Res. 16, 1208–1221 36 Otto, S.J., McCorkle, S.R., Hover, J., Conaco, C., Han, J.J., Impey, S., Yochum, G.S., Dunn, J.J., Goodman, R.H. and Mandel, G. (2007) A new binding motif for the transcriptional repressor REST uncovers large gene networks devoted to neuronal functions. J. Neurosci. 27, 6729–6739 37 Johnson, R., Gamblin, R.J., Ooi, L., Bruce, A.W., Donaldson, I.J., Westhead, D.R., Wood, I.C., Jackson, R.M. and Buckley, N.J. (2006) Identification of the REST regulon reveals extensive transposable element-mediated binding site duplication. Nucleic Acids Res. 34, 3862–3877 38 Altar, C.A., Cai, N., Bliven, T., Juhasz, M., Conner, J.M., Acheson, A.L., Lindsay, R.M. and Wiegand, S.J. (1997) Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389, 856–860 39 Shimojo, M. (2008) Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150 Glued. J. Biol. Chem. 283, 34880–34886 40 Narain, Y., Wyttenbach, A., Rankin, J., Furlong, R.A. and Rubinsztein, D.C. (1999) A molecular investigation of true dominance in Huntington’s disease. J. Med. Genet. 36, 739–746 41 Zeron, M.M., Hansson, O., Chen, N., Wellington, C.L., Leavitt, B.R., Brundin, P., Hayden, M.R. and Raymond, L.A. (2002) Increased sensitivity to N-methyl-d-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron 33, 849–860

42 Shin, J.Y., Fang, Z.H., Yu, Z.X., Wang, C.E., Li, S.H. and Li, X.J. (2005) Expression of mutant Huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 171, 1001–1012 43 Dragatsis, I., Levine, M.S. and Zeitlin, S. (2000) Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat. Genet. 26, 300–306 44 Cha, J.H. (2007) Transcriptional signatures in Huntington’s disease. Prog. Neurobiol. 83, 228–248 45 Zuccato, C. and Cattaneo, E. (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol. 5, 311–322 46 Kosik, K.S. (2006) The neuronal microRNA system. Nat. Rev. Neurosci. 7, 911–920 47 Bak, M., Silahtaroglu, A., Moller, M., Christensen, M., Rath, M.F., Skryabin, B., Tommerup, N. and Kauppinen, S. (2008) MicroRNA expression in the adult mouse central nervous system. RNA 14, 432–444 48 Krichevsky, A.M., King, K.S., Donahue, C.P., Khrapko, K. and Kosik, K.S. (2003) A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 9, 1274–1281 49 Krichevsky, A.M., Sonntag, K.C., Isacson, O. and Kosik, K.S. (2006) Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 24, 857–864 50 Bilen, J., Liu, N., Burnett, B.G., Pittman, R.N. and Bonini, N.M. (2006) MicroRNA pathways modulate polyglutamine-induced neurodegeneration. Mol. Cell 24, 157–163 51 Savas, J.N., Makusky, A., Ottosen, S., Baillat, D., Then, F., Krainc, D., Shiekhattar, R., Markey, S.P. and Tanese, N. (2008) Huntington’s disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies. Proc. Natl. Acad. Sci. U.S.A. 105, 10820–10825 52 Conaco, C., Otto, S., Han, J.J. and Mandel, G. (2006) Reciprocal actions of REST and a microRNA promote neuronal identity. Proc. Natl. Acad. Sci. U.S.A. 103, 2422–2427 53 Wu, J. and Xie, X. (2006) Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome Biol. 7, R85 54 Bates, G.P., Mangiarini, L., Mahal, A. and Davies, S.W. (1997) Transgenic models of Huntington’s disease. Hum. Mol. Genet. 6, 1633–1637 55 Lim, L.P., Lau, N.C., Garrett-Engele, P., Grimson, A., Schelter, J.M., Castle, J., Bartel, D.P., Linsley, P.S. and Johnson, J.M. (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773

Received 27 July 2009 doi:10.1042/BST0371270

 C The

C 2009 Biochemical Society Authors Journal compilation 

1275