Zinc-Finger Proteins in Brain Development and Mental Illness

Li, Hong; Lu, Ming–Wei; Liu, Xiaoyan

doi:10.21767/2573-5349.100017

Cited by 4 publications

(5 citation statements)

References 17 publications

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“…Zinc finger domain containing transcription factor are the most abundant proteins whose function are extraordinarily diverse and include epithelium development, neo-cortex development, transcription activation, regulation of apoptosis, protein folding and assembly [13–14]. Dip2a is thought to be a transcription factor due to its zinc finger motif [2].…”

Section: Resultsmentioning

confidence: 99%

Transcriptome profiling of mouse brain and lung under Dip2a regulation using RNA-sequencing

et al. 2019

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Disconnected interacting protein 2 homolog A (DIP2A) is highly expressed in nervous system and respiratory system of developing embryos. However, genes regulated by Dip2a in developing brain and lung have not been systematically studied. Transcriptome of brain and lung in embryonic 19.5 day (E19.5) were compared between wild type and Dip2a -/- mice. An average of 50 million reads per sample was mapped to the reference sequence. A total of 214 DEGs were detected in brain (82 up and 132 down) and 1900 DEGs in lung (1259 up and 641 down). GO enrichment analysis indicated that DEGs in both Brain and Lung were mainly enriched in biological processes ‘DNA-templated transcription and Transcription from RNA polymerase II promoter’, ‘multicellular organism development’, ‘cell differentiation’ and ‘apoptotic process’. In addition, COG classification showed that both were mostly involved in ‘Replication, Recombination, and Repair’, ‘Signal transduction and mechanism’, ‘Translation, Ribosomal structure and Biogenesis’ and ‘Transcription’. KEGG enrichment analysis showed that brain was mainly enriched in ‘Thyroid cancer’ pathway whereas lung in ‘Complement and Coagulation Cascades’ pathway. Transcription factor (TF) annotation analysis identified Zinc finger domain containing (ZF) proteins were mostly regulated in lung and brain. Interestingly, study identified genes Skor2 , Gpr3711 , Runx1 , Erbb3 , Frmd7 , Fut10 , Sox11 , Hapln1 , Tfap2c and Plxnb3 from brain that play important roles in neuronal cell maturation, differentiation, and survival; genes Hoxa5 , Eya1 , Errfi1 , Sox11 , Shh , Igf1 , Ccbe1 , Crh , Fgf9 , Lama5 , Pdgfra , Ptn , Rbp4 and Wnt7a from lung are important in lung development. Expression levels of the candidate genes were validated by qRT-PCR. Genome wide transcriptional analysis using wild type and Dip2a knockout mice in brain and lung at embryonic day 19.5 (E19.5) provided a genetic basis of molecular function of these genes.

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Section: Resultsmentioning

confidence: 99%

Transcriptome profiling of mouse brain and lung under Dip2a regulation using RNA-sequencing

et al. 2019

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“…K-ZNF clustering in the near region of the chromosome may imply that these K-ZNFs are involved in a similar functional category. Indeed, ZNF proteins play a functional role in maintaining brain physiology and are associated with neuronal disorders 4 – 9 . In the process of elucidating the functional role of K-ZNFs in the brain, we found that Zfp212 is highly expressed in the Cb and endogenously expressed in Purkinje cells.…”

Section: Discussionmentioning

confidence: 99%

“…ZNF238/Rp58 is involved in neocortex development and is crucial for cerebellar growth and organization and early development of GABAergic and glutamatergic cerebellar neurons 6 – 8 . Genome-wide association studies have shown that many ZNF genes are also associated with mental illnesses, such as schizophrenia, bipolar disease, and intellectual disability 9 .…”

Section: Introductionmentioning

confidence: 99%

Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation

Khang

Kang

et al. 2021

Sci Rep

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Although Krüppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain; it was mainly expressed in the cerebellum (Cb). Zfp212 (mouse homolog of human ZNF212) knockout (Zfp212-KO) mice showed a reduction in survival rate compared to wild-type mice after 20 months of age. GABAergic Purkinje cell degeneration in the Cb and aberrant locomotion were observed in adult Zfp212-KO mice. To identify genes related to the ataxia-like phenotype of Zfp212-KO mice, 39 ataxia-associated genes in the Cb were monitored. Substantial alterations in the expression of ataxin 10, protein phosphatase 2 regulatory subunit beta, protein kinase C gamma, and phospholipase D3 (Pld3) were observed. Among them, Pld3 alone was tightly regulated by Flag-tagged ZNF212 overexpression or Zfp212 knockdown in the HT22 cell line. The Cyclic Amplification and Selection of Targets assay identified the TATTTC sequence as a recognition motif of ZNF212, and these motifs occurred in both human and mouse PLD3 gene promoters. Adeno-associated virus-mediated introduction of human ZNF212 into the Cb of 3-week-old Zfp212-KO mice prevented Purkinje cell death and motor behavioral deficits. We confirmed the reduction of Zfp212 and Pld3 in the Cb of an alcohol-induced cerebellar degeneration mouse model, suggesting that the ZNF212–PLD3 relationship is important for Purkinje cell survival.

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“…Differentially expressed genes (DEGs) with a threshold FDR adjusted, p value<0.001 and fold change ≥ 2 (log2> ±1) were selected for further analysis. Gene Ontology (GO) enrichment analysis of DEGs was implemented by GOseq R packages [17]. KOBAS was used to test the statistical enrichment of DEGs in KEGG pathways.…”

Section: Methodsmentioning

confidence: 99%

Transcriptome Profiling of Mouse Brain and Lung under Dip2A Regulation Using RNA-Sequencing

Sah

Yang

Bah

et al. 2019

Preprint

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14Disconnected interacting 2 homolog A (DIP2A) gene is highly 15 expressed in nervous system and respiratory system of developing 16 embryos. However, genes regulated by Dip2a in developing brain and 17 lung have not been systemically studied. Transcriptome of brain and lung 18 in embryonic 19.5 day (E19.5) were compared between wild type and 19 Dip2a -/mice. Total RNAs were extracted from brain and lung of E19.5 20 embryos for RNA-Seq. Clean reads were mapped to mouse reference 21 sequence (mm9) using Tophat and assembled into transcripts by 22 Cufflinks. Edge R and DESeq were applied to identify differentially 2 23 expressed genes (DEGs) and annotated under GO, COG, KEGG and TF. 24An average of 50 million reads per sample was mapped to the reference 25 sequence. A total of 214 DEGs were detected in brain (82 up and 132 26 down) and 1900 DEGs in lung (1259 up and 641 down). GO enrichment 27 analysis indicated that DEGs in both Brain and Lung were mainly 28 enriched in biological processes 'DNA-templated transcription and 29 Transcription from RNA polymerase II promoter', 'multicellular 30 organism development', 'cell differentiation' and 'apoptotic process'. In 31 addition, COG classification showed that both were mostly involved in 32 'Replication, Recombination and Repair', 'Signal transduction and 33 mechanism', 'Translation, Ribosomal structure and Biogenesis' and 34 'Transcription'. KEGG enrichment analysis showed that brain was 35 mainly enriched in 'Thryoid cancer' pathway whereas lung in 36 'Complement and Coagulation Cascades' pathway. Transcription factor 37 (TF) annotation analysis identified Zinc finger domain containing (ZF) 38 proteins were mostly regulated in lung and brain. Interestingly, study 39 identified genes Skor2, Gpr3711, Runx1, Erbb3, Frmd7, Fut10, Sox11, 40 Hapln1, Tfap2c and Plxnb3 from brain that play important roles in 41 neuronal cell maturation, differentiation and survival; genes Hoxa5, 42 Eya1, Ctsh, Erff1, Lama1, Lama2, Rspo2, Sox11, Spry4, Shh, Igf1 and 43 Wnt7a from lung are important in lung development and morphogenesis. 44 Expression levels of the candidate genes were validated by qRT-PCR. 3 45 Genome wide transcriptional analysis using wild type and Dip2a 46 knockout mice in brain and lung at embryonic day 19.5 (E19.5) provided 47 [7-9]. These all evidence strongly supports the role of Dip2a gene in both 65 vertebrate and invertebrate nervous system development. However, 66 which biological process or molecular function is regulated by Dip2a 4 67 gene during embryonic brain development is not known. 68 In order to systematically understand expression pattern and 69 physiological role of Dip2a gene, Dip2a-LacZ knockin and Dip2a 65kb 70 knockout (Dip2a -/-) mouse models were generated using CRISPR/Cas9 71 system [10]. Dip2a expression via endogenous expression of 72 β-Galactosidase gene (LacZ) have shown that Dip2a is highly expressed 73 in brain neurons, retinal ganglia cell, reproductive, vascular and Lung 74 tissue in adult and ectodermal tissue in developing embryos [11]...

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Zinc-Finger Proteins in Brain Development and Mental Illness

Cited by 4 publications

References 17 publications

Transcriptome profiling of mouse brain and lung under Dip2a regulation using RNA-sequencing

Transcriptome profiling of mouse brain and lung under Dip2a regulation using RNA-sequencing

Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation

Transcriptome Profiling of Mouse Brain and Lung under Dip2A Regulation Using RNA-Sequencing

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