Altered enhancer transcription underlies Huntington’s disease striatal transcriptional signature

Gras, Stéphanie Le; Keime, Céline; Anthony, Anne; Lotz, Caroline; Longprez, Lucie de; Brouillet, Emmanuel; Cassel, Jean‐Christophe; Boutillier, Anne‐Laurence; Mérienne, Karine

doi:10.1038/srep42875

Cited by 44 publications

(36 citation statements)

References 49 publications

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“…Analysing 44 human HD brains, Hodges and coworkers observed a significant decrease in GPR6 expression compared to unaffected controls (Hodges et al 2006). Similarly, in a recent study of striatal transcriptional alterations in HD, the authors detected that the expression of GPR6 eRNA (enhancer RNA) is deregulated in R6/1 HD mouse striatum (Le Gras et al 2017). They further demonstrated that GPR6 expression is reduced in the striatum of R6/1 and Q140 HD mice models.…”

Section: Biological Relevancementioning

confidence: 74%

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Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Morales

Isawi

Reggio

2018

Drug Metabolism Reviews

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GPR3, GPR6 and GPR12 are three orphan receptors that belong to the Class A family of G protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship GPR3, GPR6 and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data is required to confirm this association. GPR3, GPR6 and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6 and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer’s disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets.

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Section: Biological Relevancementioning

confidence: 74%

“…Two independent research groups provided evidence of the relation between GPR6 and the HD pathology (Hodges et al 2006; Le Gras et al 2017). Analysing 44 human HD brains, Hodges and coworkers observed a significant decrease in GPR6 expression compared to unaffected controls (Hodges et al 2006).…”

Section: Biological Relevancementioning

confidence: 99%

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Morales

Isawi

Reggio

2018

Drug Metabolism Reviews

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“…Very few studies investigated histone acetylation in pathological context at the genome‐wide level. Our recent studies showed selective decreased H3K27ac at neuronal identity genes regulated by a super‐enhancer, in the striatum of Huntington's disease mice (Achour et al , ; Le Gras et al , ). In the hippocampus of the CK‐p25 AD mouse model, H3K27ac levels were decreased at promoter/enhancers of genes associated with synapse and learning functions and preferentially bound by CBP (Gjoneska et al , ).…”

Section: Discussionmentioning

confidence: 99%

Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator

et al. 2018

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Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity (LTD, dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP‐TTK21, a small‐molecule activator of CBP/p300 histone acetyltransferases (HAT). At the transcriptional level, CSP‐TTK21 re‐established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers. At the epigenomic level, the hippocampus of tauopathic mice showed a significant decrease in H2B but not H3K27 acetylation levels, both marks co‐localizing at TSS and CBP enhancers. Importantly, CSP‐TTK21 treatment increased H2B acetylation levels at decreased peaks, CBP enhancers, and TSS, including genes associated with plasticity and neuronal functions, overall providing a 95% rescue of the H2B acetylome in tauopathic mice. This study is the first to provide in vivo proof‐of‐concept evidence that CBP/p300 HAT activation efficiently reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated with Alzheimer's disease lesions in mice.

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“…Increasingly evidences implicate that enhancers are functionally important in key cellular processes including cell development, differentiation and apoptosis. eRNAs are generated by the transcription of active enhancers and involve in the development of various diseases by regulating the expression of multiple genes . GREB1 is shown to be one of the most oestrogen‐specific genes and plays an important role in oestrogen‐mediated transcriptional activation.…”

Section: Discussionmentioning

confidence: 99%

“…For the group of eGREB1 knockdown with oestrogen treatment, the cell proliferation was obviously decreased ( Figure 3A, B, P < 0.01 in T24 and 5637); the cell migration ratio were reduced by 11.68% in T24 and 18.28% in 5637 ( Figure 3C-E, P < 0.001 in T24 and 5637); the invasive ability of the cells is also prominently weakened ( Figure 4A-C, P < 0.01 in T24 and 5637); ELISA assay showed that the activity of caspase-3 were increased ( Figure 4E, P = 0.001 in T24, by regulating the expression of multiple genes. [22][23][24][25][26] GREB1 is shown to be one of the most oestrogen-specific genes and plays an important role in oestrogen-mediated transcriptional activation. The corresponding enhancer of GREB1 could transcribe into eGREB1 when exposed to oestrogen.…”

Section: Egreb1 Knockdown Attenuated the Cancer-promoting Effect Ofmentioning

confidence: 99%

Oestrogen promotes tumorigenesis of bladder cancer by inducing the enhancer RNA—eGREB1

Ding

Liu

et al. 2018

J Cellular Molecular Medi

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In recent years, studies have shown that enhancer RNAs (eRNAs) can be transcribed from enhancers. Increasing evidence has revealed that eRNAs play critical roles in the development of various cancers. Oestrogen‐associated eRNAs are closely related to breast cancer. In view of the gender differences in bladder cancer (BCa), we suppose that oestrogen‐associated eRNAs are also involved in tumorigenesis of BCa. In our study, we first demonstrated that eGREB1 derived from the enhancer of an oestrogen‐responsive gene—GREB1 was up‐regulated in BCa tissues, and the expression level of eGREB1 is positively associated with the histological grade and TNM stage of BCa. Knockdown of eGREB1 by CRISPR‐Cas13a could inhibit cell proliferation, migration and invasion and induce apoptosis in BCa cells T24 and 5637. Besides, we exhibited the promoting effect of oestrogen on BCa cells. What's more, down‐regulation of eGREB1 could improve the malignant biological characteristics of BCa cells induced by oestrogen. In conclusion, our data indicated that eGREB1 plays oncogenic role and oestrogen may promote the occurrence and progression of BCa by inducing eGREB1 production. Our findings provide new insights into the prevention of BCa and develop a novel therapeutic target for the treatment of BCa.

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Altered enhancer transcription underlies Huntington’s disease striatal transcriptional signature

Cited by 44 publications

References 49 publications

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator

Oestrogen promotes tumorigenesis of bladder cancer by inducing the enhancer RNA—eGREB1

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