PMID- 25905630 OWN - NLM STAT- MEDLINE DCOM- 20160119 LR - 20220408 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 4 DP - 2015 TI - ZNF804A Transcriptional Networks in Differentiating Neurons Derived from Induced Pluripotent Stem Cells of Human Origin. PG - e0124597 LID - 10.1371/journal.pone.0124597 [doi] LID - e0124597 AB - ZNF804A (Zinc Finger Protein 804A) has been identified as a candidate gene for schizophrenia (SZ), autism spectrum disorders (ASD), and bipolar disorder (BD) in replicated genome wide association studies (GWAS) and by copy number variation (CNV) analysis. Although its function has not been well-characterized, ZNF804A contains a C2H2-type zinc-finger domain, suggesting that it has DNA binding properties, and consequently, a role in regulating gene expression. To further explore the role of ZNF804A on gene expression and its downstream targets, we used a gene knockdown (KD) approach to reduce its expression in neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs). KD was accomplished by RNA interference (RNAi) using lentiviral particles containing shRNAs that target ZNF804A mRNA. Stable transduced NPC lines were generated after puromycin selection. A control cell line expressing a random (scrambled) shRNA was also generated. Neuronal differentiation was induced, RNA was harvested after 14 days and transcriptome analysis was carried out using RNA-seq. 1815 genes were found to be differentially expressed at a nominally significant level (p<0.05); 809 decreased in expression in the KD samples, while 1106 increased. Of these, 370 achieved genome wide significance (FDR<0.05); 125 were lower in the KD samples, 245 were higher. Pathway analysis showed that genes involved in interferon-signaling were enriched among those that were down-regulated in the KD samples. Correspondingly, ZNF804A KD was found to affect interferon-alpha 2 (IFNA2)-mediated gene expression. The findings suggest that ZNF804A may affect a differentiating neuron's response to inflammatory cytokines, which is consistent with models of SZ and ASD that support a role for infectious disease, and/or autoimmunity in a subgroup of patients. FAU - Chen, Jian AU - Chen J AD - Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Lin, Mingyan AU - Lin M AD - Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Hrabovsky, Anastasia AU - Hrabovsky A AD - Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Pedrosa, Erika AU - Pedrosa E AD - Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Dean, Jason AU - Dean J AD - Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Jain, Swati AU - Jain S AD - Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Zheng, Deyou AU - Zheng D AD - Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America; Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Lachman, Herbert M AU - Lachman HM AD - Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America; Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America. LA - eng SI - GEO/GSE54112 GR - MH073164/MH/NIMH NIH HHS/United States GR - R21 MH087840/MH/NIMH NIH HHS/United States GR - R01 MH073164/MH/NIMH NIH HHS/United States GR - MH099427/MH/NIMH NIH HHS/United States GR - MH087840/MH/NIMH NIH HHS/United States GR - R01 MH099427/MH/NIMH NIH HHS/United States GR - R33 MH087840/MH/NIMH NIH HHS/United States GR - MH097893/MH/NIMH NIH HHS/United States GR - R21 MH097893/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150423 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Kruppel-Like Transcription Factors) RN - 0 (ZNF804A protein, human) SB - IM MH - *Cell Differentiation MH - Cell Line MH - Gene Knockdown Techniques MH - *Gene Regulatory Networks MH - Humans MH - Induced Pluripotent Stem Cells/*cytology MH - Kruppel-Like Transcription Factors/*genetics MH - Neurons/*cytology MH - RNA Interference MH - *Transcription, Genetic PMC - PMC4408091 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2015/04/24 06:00 MHDA- 2016/01/20 06:00 PMCR- 2015/04/23 CRDT- 2015/04/24 06:00 PHST- 2014/07/07 00:00 [received] PHST- 2015/03/16 00:00 [accepted] PHST- 2015/04/24 06:00 [entrez] PHST- 2015/04/24 06:00 [pubmed] PHST- 2016/01/20 06:00 [medline] PHST- 2015/04/23 00:00 [pmc-release] AID - PONE-D-14-29675 [pii] AID - 10.1371/journal.pone.0124597 [doi] PST - epublish SO - PLoS One. 2015 Apr 23;10(4):e0124597. doi: 10.1371/journal.pone.0124597. eCollection 2015.