Ribosomal transcription is regulated by PGC-1alpha and disturbed in Huntington’s disease

Jesse, Sarah; Bayer, Hanna; Alupei, Marius Costel; Zügel, Martina; Mulaw, Medhanie A.; Tuorto, Francesca; Malmsheimer, Silke; Singh, Karmveer; Steinacker, Jürgen M.; Schümann, Uwe; Ludolph, Albert C.; Scharffetter‐­Kochanek, Karin; Witting, Anke; Weydt, Patrick; Iben, Sebastian

doi:10.1038/s41598-017-09148-7

Cited by 31 publications

(18 citation statements)

References 37 publications

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“…As expected, and through the enrichment analysis, PPARGC1A was found to be associated with the regulation of progesterone synthesized in the biosynthetic pathway ( Supplementary Figure S1B). The deregulation of transcription and mitochondrial function caused by PPARGC1A is associated with conditions such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease (Weydt et al, 2006;Eschbach et al, 2013;Jesse et al, 2017). Additionally, the second H-B, CTBP1 plays a role in the regulation of gene expression during embryonic development, as well as participation in axial patterning and cellular proliferation and differentiation (Hildebrand and Soriano, 2002;Van Hateren et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Candidate Genes Associated With Neurological Findings in a Patient With Trisomy 4p16.3 and Monosomy 5p15.2

et al. 2020

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In this report, we present a patient with brain alterations and dysmorphic features associated with chromosome duplication seen in 4p16.3 region and chromosomal deletion in a critical region responsible for Cri-du-chat syndrome (CdCS). Chromosomal microarray analysis (CMA) revealed a 41.1 Mb duplication encompassing the band region 4p16.3-p13, and a 14.7 Mb deletion located between the bands 5p15.33 and p15.1. The patient's clinical findings overlap with previously reported cases of chromosome 4p duplication syndrome and CdCS. The patient's symptoms are notably similar to those of CdCS patients as she presented with a weak, high-pitched voice and showed a similar pathogenicity observed in the brain MRI. These contiguous gene syndromes present with distinct clinical manifestations. However, the phenotypic and cytogenetic variability in affected individuals, such as the low frequency and the large genomic regions that can be altered, make it challenging to identify candidate genes that contribute to the pathogenesis of these syndromes. Therefore, systems biology and CMA techniques were used to investigate the extent of chromosome rearrangement on critical regions in our patient's phenotype. We identified the candidate genes PPARGC1A, CTBP1, TRIO, TERT, and CCT5 that are associated with the neuropsychomotor delay, microcephaly, and neurological alterations found in our patient. Through investigating pathways that associate with essential nodes in the protein interaction network, we discovered proteins involved in cellular differentiation and proliferation, as well as proteins involved in the formation and disposition of the cytoskeleton. The combination of our cytogenomic and bioinformatic analysis provided these possible explanations for the unique clinical phenotype, which has not yet been described in scientific literature.

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Section: Discussionmentioning

confidence: 99%

Candidate Genes Associated With Neurological Findings in a Patient With Trisomy 4p16.3 and Monosomy 5p15.2

et al. 2020

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“…Other, less well-investigated, human diseases are beginning to see the groundwork being laid. Ribosomal DNA expression, rDNA loss, nucleolus-mediated stress responses, and heterochromatin defects are now being connected to neurological diseases (Jesse et al 2017;Maina et al 2018;Nunez Villacis et al 2018;Sun et al 2018) -whether these are confirmed, or are found to be consequential to the disease, remains to be seen.…”

Section: Disease Phenotypes -The Real and The Potentialmentioning

confidence: 99%

The peculiar genetics of the ribosomal DNA blurs the boundaries of transgenerational epigenetic inheritance

Bughio

Maggert

2018

Chromosome Res

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Our goal is to draw a line-hypothetical in its totality but experimentally supported at each individual step-connecting the ribosomal DNA and the phenomenon of transgenerational epigenetic inheritance of induced phenotypes. The reasonableness of this hypothesis is offset by its implication, that many (or most) (or all) of the cases of induced-and-inherited phenotypes that are seen to persist for generations are instead unmapped induced polymorphisms in the ribosomal DNA, and thus are the consequence of the peculiar and enduringly-fascinating genetics of the highly-transcribed repeat DNA structure at that locus.

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“…The regulation of this gene is complex; it has multiple isoforms and alternative promoters [30] and gene expression is regulated by a variety of stimuli, including cytokines, insulin, exercise and the cold [31]. PGC-1 α can induce ribosomal transcription under stress conditions such as oxidative stress and exercise [32].…”

Section: Discussionmentioning

confidence: 99%

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease

et al. 2019

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Late onset Alzheimer’s disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer’s disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer’s Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer’s cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A ( p = 2.2 × 10 −6 ), RORA ( p = 7.4 × 10 −7 ) and ZNF423 ( p = 2.1 × 10 −6 ). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer’s disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer’s disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

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Ribosomal transcription is regulated by PGC-1alpha and disturbed in Huntington’s disease

Cited by 31 publications

References 37 publications

Candidate Genes Associated With Neurological Findings in a Patient With Trisomy 4p16.3 and Monosomy 5p15.2

Candidate Genes Associated With Neurological Findings in a Patient With Trisomy 4p16.3 and Monosomy 5p15.2

The peculiar genetics of the ribosomal DNA blurs the boundaries of transgenerational epigenetic inheritance

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease

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