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@ARTICLE{Heinzer:162908,
      author       = {Heinzer, Daniel and Avar, Merve and Pease, Daniel Patrick
                      and Dhingra, Ashutosh and Yin, Jiang-An and Schaper, Elke
                      and Doğançay, Berre and Emmenegger, Marc and Spinelli,
                      Anna and Maggi, Kevin and Chincisan, Andra and Mead, Simon
                      and Hornemann, Simone and Heutink, Peter and Aguzzi,
                      Adriano},
      title        = {{N}ovel regulators of {P}r{PC} biosynthesis revealed by
                      genome-wide {RNA} interference.},
      journal      = {PLoS pathogens},
      volume       = {17},
      number       = {10},
      issn         = {1553-7374},
      address      = {Lawrence, Kan.},
      publisher    = {PLoS},
      reportid     = {DZNE-2021-01563},
      pages        = {e1010013},
      year         = {2021},
      note         = {(CC BY)},
      abstract     = {The cellular prion protein PrPC is necessary for prion
                      replication, and its reduction greatly increases life
                      expectancy in animal models of prion infection. Hence the
                      factors controlling the levels of PrPC may represent
                      therapeutic targets against human prion diseases. Here we
                      performed an arrayed whole-transcriptome RNA interference
                      screen to identify modulators of PrPC expression. We
                      cultured human U251-MG glioblastoma cells in the presence of
                      64'752 unique siRNAs targeting 21'584 annotated human genes,
                      and measured PrPC using a one-pot fluorescence-resonance
                      energy transfer immunoassay in 51'128 individual microplate
                      wells. This screen yielded 743 candidate regulators of PrPC.
                      When downregulated, 563 of these candidates reduced and 180
                      enhanced PrPC expression. Recursive candidate attrition
                      through multiple secondary screens yielded 54 novel
                      regulators of PrPC, 9 of which were confirmed by CRISPR
                      interference as robust regulators of PrPC biosynthesis and
                      degradation. The phenotypes of 6 of the 9 candidates were
                      inverted in response to transcriptional activation using
                      CRISPRa. The RNA-binding post-transcriptional repressor
                      Pumilio-1 was identified as a potent limiter of PrPC
                      expression through the degradation of PRNP mRNA. Because of
                      its hypothesis-free design, this comprehensive
                      genetic-perturbation screen delivers an unbiased landscape
                      of the genes regulating PrPC levels in cells, most of which
                      were unanticipated, and some of which may be amenable to
                      pharmacological targeting in the context of antiprion
                      therapies.},
      keywords     = {Cell Line / Gene Expression Regulation: physiology /
                      Genome-Wide Association Study / Humans / PrPC Proteins:
                      biosynthesis / RNA Interference / RNA-Binding Proteins:
                      metabolism},
      cin          = {AG Heutink 1},
      ddc          = {610},
      cid          = {I:(DE-2719)1210002},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34705895},
      pmc          = {pmc:PMC8575309},
      doi          = {10.1371/journal.ppat.1010013},
      url          = {https://pub.dzne.de/record/162908},
}