ZNF804A transcriptional networks in differentiating neurons derived from induced pluripotent stem cells of human origin

Jian Chen, Mingyan Lin, Anastasia Hrabovsky, Erika Pedrosa, Jason Dean, Swati Jain, Deyou Zheng, Herbert M. Lachman

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 in-terferon- 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.

Original languageEnglish (US)
Article numbere0124597
JournalPLoS One
Volume10
Issue number4
DOIs
StatePublished - Apr 23 2015

Fingerprint

Induced Pluripotent Stem Cells
Gene Regulatory Networks
zinc finger motif
Zinc Fingers
Stem cells
Neurons
Zinc
neurons
Genes
Gene expression
Proteins
proteins
Gene Expression
RNA
Schizophrenia
gene expression
Stem Cells
stem cells
Gene Knockdown Techniques
genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

ZNF804A transcriptional networks in differentiating neurons derived from induced pluripotent stem cells of human origin. / Chen, Jian; Lin, Mingyan; Hrabovsky, Anastasia; Pedrosa, Erika; Dean, Jason; Jain, Swati; Zheng, Deyou; Lachman, Herbert M.

In: PLoS One, Vol. 10, No. 4, e0124597, 23.04.2015.

Research output: Contribution to journalArticle

Chen, Jian ; Lin, Mingyan ; Hrabovsky, Anastasia ; Pedrosa, Erika ; Dean, Jason ; Jain, Swati ; Zheng, Deyou ; Lachman, Herbert M. / ZNF804A transcriptional networks in differentiating neurons derived from induced pluripotent stem cells of human origin. In: PLoS One. 2015 ; Vol. 10, No. 4.
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