Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex

Hill, Matthew; Killick, Richard; Navarrete, Katherinne; Maruszak, Aleksandra; McLaughlin, Gemma M.; Williams, Brenda; Bray, Nicholas John

doi:10.1503/jpn.160073

Cited by 33 publications

(34 citation statements)

References 40 publications

(53 reference statements)

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“…Beyond the group enrichments and network analyses described above, many studies have begun to link variants to specific genes as eQTLs and experimentally follow them up to understand the biological consequences of these variants. Examples include signals near ZNF804A [103, 104], TCF4 [105], and CACNA1C [106, 107]. The most detailed and well publicized such study has been that of Sekar et al [108] in the HLA region.…”

Section: Common Low-penetrance Variants and Gwasmentioning

confidence: 99%

“…This last point is of interest as it connects ZNF804A and DPYSL2 , two genes that have no other known functional connection other than their associations with schizophrenia. Finally, Hill et al[105] knocked down the schizophrenia-associated gene TCF4 and reported that this resulted in RNA-level changes of genes involved in the cell cycle and the proliferation of human cortical progenitor cells.…”

Section: Insights From Transcriptome Studiesmentioning

confidence: 99%

“…The applications one can imagine are only limited by what is ethical to do in a lab. The small effect sizes may still be a problem, but others and we have shown that when one works with modified or edited cells, small effect variants can lead to robust cellular phenotypes [103, 105, 139, 176]. These technologies are new, and there is still much space for improvement, including editing efficiency [177], uniform and specific differentiation [178, 179], the time needed for maturation, and the faithful recapitulation of cortical circuits by organoids [180].…”

Section: Closing Remarksmentioning

confidence: 99%

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Recent Advances in the Genetics of Schizophrenia

Avramopoulos

2018

Complex Psychiatry

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The last decade brought tremendous progress in the field of schizophrenia genetics. As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include large copy number variants, rare coding inherited and de novο variants, and over 100 loci harboring common risk variants. While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory. Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups. Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes. The challenge is to apply this new knowledge to prevention and treatment and help patients. The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries.

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Section: Common Low-penetrance Variants and Gwasmentioning

confidence: 99%

Section: Insights From Transcriptome Studiesmentioning

confidence: 99%

Section: Closing Remarksmentioning

confidence: 99%

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Recent Advances in the Genetics of Schizophrenia

Avramopoulos

2018

Complex Psychiatry

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“…Probes at which gene expression in each SETD1A siRNA condition differed from the siRNA control condition were identified by individual t tests (two-tailed). Consistently with previous studies [6, 7] gene expression changes with p value <0.05 in both SETD1A knockdown conditions and a concordant direction of effect were used for all subsequent analyses.…”

Section: Methodsmentioning

confidence: 99%

Transcriptional Changes following Cellular Knockdown of the Schizophrenia Risk Gene <b><i>SETD1A</i></b> Are Enriched for Common Variant Association with the Disorder

et al. 2019

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Loss of function mutations in SETD1A are the first experiment-wide significant findings to emerge from exome sequencing studies of schizophrenia. Although SETD1Ais known to encode a histone methyltransferase, the consequences of reduced SETD1A activity on gene expression in neural cells have, to date, been unknown. To explore transcriptional changes through which genetic perturbation of SETD1A could confer risk for schizophrenia, we have performed genome-wide gene expression profiling of a commonly used human neuroblastoma cell line in which SETD1A expression has been experimentally reduced using RNA interference (RNAi). We identified 1,031 gene expression changes that were significant in two separate RNAi conditions compared with control, including effects on genes of known neurodevelopmental importance such as DCX and DLX5. Genes that were differentially expressed following SETD1A knockdown were enriched for annotation to metabolic pathways, peptidase regulator activity and integrin-mediated regulation of cell adhesion. Moreover, differentially expressed genes were enriched for common variant association with schizophrenia, suggesting a degree of molecular convergence between this rare schizophrenia risk factor and susceptibility variants for the disorder operating more generally.

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“…82 However, STAG1 has been found to be differentially expressed in a neuronal progenitor cell line derived from the developing cerebral cortex in which TCF4, a transcriptional regulator having common variants significantly associated with schizophrenia, was underexpressed. [83][84][85] TCF4 (transcription factor 4) is a schizophrenia gene. Apart from its involvement in brain development, synaptogenesis, cell cycle exit, cell proliferation and differentiation, TCF4 has been reported to be an indirect target of the VDR pathway in mammary gland of mice and in cell lines of colorectal cancer.…”

Section: Figure 5 Cinnarizine and Its Targets In The Schizophrenia Imentioning

confidence: 99%

Potentially repurposable drugs for schizophrenia identified from its interactome

Karunakaran

Chaparala

Ganapathiraju

2018

Preprint

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From the schizophrenia drug-target interactome, 1 we studied the drugs that targeted multiple proteins in the interactome, or those that target proteins with many targets, or those that target novel (computationally predicted) interactors of schizophrenia associated proteins. In schizophrenia, gene expression has been described as a measurable aspect of the disease reflecting the action of risk genes. We studied each of the selected drugs using the NextBio software suite, and shortlisted those that had a negative correlation with gene expression of schizophrenia. This analysis resulted in 12 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for schizophrenia (disorder versus normal). Some of these drugs were already being tested for their clinical activity in schizophrenia and other neuropsychiatric disorders. Several proteins in the protein interactome of the targets of several of these drugs were associated with various neuropsychiatric disorders. The network of genes which were differentially expressed on drug treatment, and had an anti-correlation with gene expression in schizophrenia, were significantly enriched in pathways relevant to schizophrenia etiology and GWAS genes associated with traits or diseases that had pathophysiological overlap with schizophrenia. Drugs that are structurally similar to the shortlisted drugs, or targeted the same genes as these drugs, have also demonstrated clinical activity in schizophrenia and other related disorders. This integrated computational analysis may help translate insights from the schizophrenia drug-protein interactome to clinical research -an important step, especially in the field of psychiatric drug development, facing a high failure rate.

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Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex

Cited by 33 publications

References 40 publications

Recent Advances in the Genetics of Schizophrenia

Recent Advances in the Genetics of Schizophrenia

Transcriptional Changes following Cellular Knockdown of the Schizophrenia Risk Gene <b><i>SETD1A</i></b> Are Enriched for Common Variant Association with the Disorder

Potentially repurposable drugs for schizophrenia identified from its interactome

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