TY - JOUR
T1 - Convergent Evidence That ZNF804A Is a Regulator of Pre-messenger RNA Processing and Gene Expression
AU - Chapman, Ria M.
AU - Tinsley, Caroline L.
AU - Hill, Matthew J.
AU - Forrest, Marc P.
AU - Tansey, Katherine E.
AU - Pardiñas, Antonio F.
AU - Rees, Elliott
AU - Doyle, A. Michelle
AU - Wilkinson, Lawrence S.
AU - Owen, Michael J.
AU - O'Donovan, Michael C.
AU - Blake, Derek J.
N1 - Funding Information:
This study was funded by a Wellcome Trust project grant (WT088866) and the Medical Research Council (Grant No. MR/L010305/1). Chapman and Forrest were funded by Medical Research Council PhD studentships.
Publisher Copyright:
© 2018 The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
PY - 2019/10/24
Y1 - 2019/10/24
N2 - Genome-wide association studies have linked common variation in ZNF804A with an increased risk of schizophrenia. However, little is known about the biology of ZNF804A and its role in schizophrenia. Here, we investigate the function of ZNF804A using a variety of complementary molecular techniques. We show that ZNF804A is a nuclear protein that interacts with neuronal RNA splicing factors and RNA-binding proteins including RBFOX1, which is also associated with schizophrenia, CELF3/4, components of the ubiquitin-proteasome system and the ZNF804A paralog, GPATCH8. GPATCH8 also interacts with splicing factors and is localized to nuclear speckles indicative of a role in pre-messenger RNA (mRNA) processing. Sequence analysis showed that GPATCH8 contains ultraconserved, alternatively spliced poison exons that are also regulated by RBFOX proteins. ZNF804A knockdown in SH-SY5Y cells resulted in robust changes in gene expression and pre-mRNA splicing converging on pathways associated with nervous system development, synaptic contact, and cell adhesion. We observed enrichment (P = 1.66 × 10-9) for differentially spliced genes in ZNF804A-depleted cells among genes that contain RBFOX-dependent alternatively spliced exons. Differentially spliced genes in ZNF804A-depleted cells were also enriched for genes harboring de novo loss of function mutations in autism spectrum disorder (P = 6.25 × 10-7, enrichment 2.16) and common variant alleles associated with schizophrenia (P =. 014), bipolar disorder and schizophrenia (P =. 003), and autism spectrum disorder (P =. 005). These data suggest that ZNF804A and its paralogs may interact with neuronal-splicing factors and RNA-binding proteins to regulate the expression of a subset of synaptic and neurodevelopmental genes.
AB - Genome-wide association studies have linked common variation in ZNF804A with an increased risk of schizophrenia. However, little is known about the biology of ZNF804A and its role in schizophrenia. Here, we investigate the function of ZNF804A using a variety of complementary molecular techniques. We show that ZNF804A is a nuclear protein that interacts with neuronal RNA splicing factors and RNA-binding proteins including RBFOX1, which is also associated with schizophrenia, CELF3/4, components of the ubiquitin-proteasome system and the ZNF804A paralog, GPATCH8. GPATCH8 also interacts with splicing factors and is localized to nuclear speckles indicative of a role in pre-messenger RNA (mRNA) processing. Sequence analysis showed that GPATCH8 contains ultraconserved, alternatively spliced poison exons that are also regulated by RBFOX proteins. ZNF804A knockdown in SH-SY5Y cells resulted in robust changes in gene expression and pre-mRNA splicing converging on pathways associated with nervous system development, synaptic contact, and cell adhesion. We observed enrichment (P = 1.66 × 10-9) for differentially spliced genes in ZNF804A-depleted cells among genes that contain RBFOX-dependent alternatively spliced exons. Differentially spliced genes in ZNF804A-depleted cells were also enriched for genes harboring de novo loss of function mutations in autism spectrum disorder (P = 6.25 × 10-7, enrichment 2.16) and common variant alleles associated with schizophrenia (P =. 014), bipolar disorder and schizophrenia (P =. 003), and autism spectrum disorder (P =. 005). These data suggest that ZNF804A and its paralogs may interact with neuronal-splicing factors and RNA-binding proteins to regulate the expression of a subset of synaptic and neurodevelopmental genes.
KW - RNA-binding proteins
KW - alternative splicing
KW - autism spectrum disorder
KW - gene expression
KW - neurodevelopment
KW - schizophrenia
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U2 - 10.1093/schbul/sby183
DO - 10.1093/schbul/sby183
M3 - Article
C2 - 30597088
AN - SCOPUS:85073050218
SN - 0586-7614
VL - 45
SP - 1267
EP - 1278
JO - Schizophrenia bulletin
JF - Schizophrenia bulletin
IS - 6
ER -
