DNA methylation of a novel regulatory element within the tyrosine hydroxylase gene (TH) is dysregulated by chronic cocaine dependence in the human striatum
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ABSTRACT:
PROVIDER: PRJNA756973 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15566621.fastq.gz | Fastqsanger.gz | |||
| SRR15566622.fastq.gz | Fastqsanger.gz | |||
| SRR15566623.fastq.gz | Fastqsanger.gz | |||
| SRR15566624.fastq.gz | Fastqsanger.gz | |||
| SRR15566625.fastq.gz | Fastqsanger.gz |
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Project description:Pathogenic variants of the J-domain protein DNAJC12, a co-chaperone of Hsp70, cause parkinsonism, which seems associated with a defective interaction of DNAJC12 with tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis. Here, we report the characterization of TH:DNAJC12 complex formation and show that DNAJC12 binding stabilizes TH and delays its time-dependent aggregation in an Hsp70-independent manner, while maintaining TH activity and regulatory inhibition by dopamine. Interestingly, although neither TH nor DNAJC12 alone significantly [MDT1] [AM2] activate Hsc70, the complex stimulates [AM3] its ATPase activity. Cryoelectron microscopy reveals two DNAJC12 monomers bound per TH tetramer, each embracing one of the two regulatory domain dimers, leaving all active sites available for substrate and dopamine interaction. Biochemical data confirm the key role of the DNAJC12 last eight residues in TH binding, explaining the molecular disease mechanism of C-terminal truncated DNAJC12 variants.
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Project description:Generation of midbrain dopaminergic (mDA) neurons from human pluripotent stem cells provides a platform for inquiry into basic and translational studies of Parkinson’s disease (PD). However, heterogeneity in differentiation in vitro makes it difficult to identify mDA neurons in culture or in vivo following transplantation. Tyrosine hydroxylase (TH), the first and rate-limiting enzyme for dopamine synthesis, is a well-established marker for mDA neurons. Here, we report the generation of a human embryonic stem cell (hESC) line with a TH-RFP (red fluorescent protein) that was generated via insertion of an RFP sequence downstream of the TH coding sequence. We validated that endogenous TH expression was unaffected by genetic modification; RFP faithfully mimicked TH expression during differentiation. Use of this TH-RFP reporter cell line enabled purification of mDA-like neurons from heterogeneous cultures with subsequent characterization of neuron transcriptional and epigenetic programs (global binding profiles of H3K27ac, H3K4me1 and 5 hydroxymethylcytosine (5hmC)) at four different stages of development. We anticipate that tools and data described here will contribute to development of mDA neurons for applications in disease modeling and/or drug screening and cell replacement therapies for PD.
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2015-07-04 | E-GEOD-67281 | biostudies-arrayexpress
Project description:DNA from four cattle breeds was used to re-sequence all of the exons and 56% of the introns of the bovine tyrosine hydroxylase (TH) gene and 97% and 13% of the bovine dopamine β-hydroxylase (DBH) coding and non-coding sequences, respectively. Two novel single nucleotide polymorphisms (SNPs) and a microsatellite motif were found in the TH sequences. The DBH sequences contained 62 nucleotide changes, including eight non-synonymous SNPs (nsSNPs) that are of particular interest because they may alter protein function and therefore affect the phenotype. These DBH nsSNPs resulted in amino acid substitutions that were predicted to destabilize the protein structure. Six SNPs (one from TH and five from DBH non-synonymous SNPs) were genotyped in 140 animals; all of them were polymorphic and had a minor allele frequency of > 9%. There were significant differences in the intra- and inter-population haplotype distributions. The haplotype differences between Brahman cattle and the three B. t. taurus breeds (Charolais, Holstein and Lidia) were interesting from a behavioural point of view because of the differences in temperament between these breeds.
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