Role of the small subunit processome in the maintenance of pluripotent stem cells

You, Kwon Tae; Park, Joha; Kim, V. Narry

doi:10.1101/gad.267112.115

Cited by 77 publications

(80 citation statements)

References 40 publications

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“…We have discussed above the role of EFEMP1 in the ECM. The other relevant genes are: WDR75, which reduces the expression of homeobox NANOG 62 and was associated with T2* in the pallidum (rs6740926, Pmin=1.31E-14, cluster 5); ZIC4 (exon) which can lead to cerebellar malformations and was found associated with multiple rfMRI connections mainly between prefrontal, cerebellar and parietal areas (rs2279829, P=8.34E-12, cluster 8); ZIP8 (see above) which plays a role in brain development via release from choroid plexus; NR2F1-AS1 (COUP-TF1), a master regulator which interacts with PAX6 (rs7442779, P=8.18E-15, cluster 12); HBEGF which stimulates neurogenesis in proliferative zones of the adult brain (see above); WNT16 (rs2536185, Pmin=1.30E-16, cluster 17); ALDH1A2 (cluster 33, see above)…”

Section: -64 Of Supplementarymentioning

confidence: 99%

Genome-wide association studies of brain structure and function in the UK Biobank

Elliott

Sharp

Alfaro-Almagro

et al. 2017

Preprint

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The genetic basis of brain structure and function is largely unknown. We carried out genome-wide association studies (GWAS) of 3,144 distinct functional and structural brain imaging derived phenotypes (IDPs), using imaging and genetic data from a total of 9,707 participants in UK Biobank. All subjects were imaged on a single scanner, with 6 distinct brain imaging modalities being acquired. We show that most of the IDPs are heritable and we identify patterns of coheritability within and between IDP sub-classes. We report 1,262 SNP associations with IDPs, based on a discovery sample of 8,426 subjects. Notable significant and interpretable associations include: spatially specific changes in T2* in subcortical regions associated with several genes related to iron transport and storage; spatially extended changes in white matter micro-structure and lesion volume associated with genes coding for proteins of the extracellular matrix and the epidermal growth factor; variations in pontine crossing tract organization associated with genes that regulate axon guidance and fasciculation during development; and more broadly, variations in brain imaging measures associated with 14 genes involved in development, pathway signalling and plasticity, including overlap with 6 genes contributing to transport of nutrients and minerals. Our results provide new insight into the genetic architecture of the brain with relevance to complex neurological and psychiatric disorders, as well as brain development and aging.

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Section: -64 Of Supplementarymentioning

confidence: 99%

Genome-wide association studies of brain structure and function in the UK Biobank

Elliott

Sharp

Alfaro-Almagro

et al. 2017

Preprint

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“…Furthermore, ESCs require high global translational rates to maintain their pluripotency7. These observations raise an intriguing question: how do ESCs maintain the quality of their proteome under enhanced protein synthesis and proliferation rates?…”

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confidence: 99%

Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan

et al. 2016

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Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly. Moreover, increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein. We further show that increased expression of CCT8 in somatic tissues extends Caenorhabditis elegans lifespan in a TRiC/CCT-dependent manner. Ectopic expression of CCT8 also ameliorates the age-associated demise of proteostasis and corrects proteostatic deficiencies in worm models of Huntington's disease. Our results suggest proteostasis is a common principle that links organismal longevity with hESC immortality.

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“…Cellular proteostasis relies on the interplay of protein synthesis with diverse chaperone classes and clearance systems (Figure 3B). Unlike what is observed upon differentiation of embryonic stem cells (ESCs), which leads to higher translation (Ingolia et al, 2011; Sampath et al, 2008; You et al, 2015), NSPC differentiation led to an overall decline in transcripts encoding ribosomal subunits, indicative of translation attenuation (Figures 3B, S3A). Direct measurements of bulk protein synthesis using fluorescent O-propargyl-puromycin (OPP) labeling of newly translated proteins confirmed translation is reduced in the neural progeny (Figures 3C, S3B).…”

Section: Resultsmentioning

confidence: 84%

Differentiation drives widespread rewiring of the neural stem cell chaperone network

Vonk

Rainbolt

Dolan

et al. 2020

Preprint

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SummaryNeural stem and progenitor cells (NSPCs) are critical for continued cellular replacement in the adult brain. Life-long maintenance of a functional NSPC pool necessitates stringent mechanisms to preserve a pristine proteome. We find that the NSPCs chaperone network robustly maintains misfolded protein solubility and stress resilience through high levels of the ATP-dependent chaperonin TRiC/CCT. Strikingly, NSPC differentiation rewires the cellular chaperone network, reducing TRiC/CCT levels and inducing those of the ATP-independent small heat shock proteins (sHSPs). This switches the proteostasis strategy in neural progeny cells to promote sequestration of misfolded proteins into protective inclusions. The chaperone network of NSPCs is more effective than that of differentiated cells, leading to improved management of proteotoxic stress and amyloidogenic proteins. However, NSPC proteostasis is impaired by brain aging. The less efficient chaperone network of differentiated neural progeny may contribute to their enhanced susceptibility to neurodegenerative diseases characterized by aberrant protein misfolding and aggregation.

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Role of the small subunit processome in the maintenance of pluripotent stem cells

Cited by 77 publications

References 40 publications

Genome-wide association studies of brain structure and function in the UK Biobank

Genome-wide association studies of brain structure and function in the UK Biobank

Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan

Differentiation drives widespread rewiring of the neural stem cell chaperone network

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