• ISSN 1674-8301
  • CN 32-1810/R
Volume 36 Issue 4
Jul.  2022
Turn off MathJax
Article Contents
Yuanyuan Wang, Liya Liu, Mingyan Lin. Psychiatric risk gene transcription factor 4 preferentially regulates cortical interneuron neurogenesis during early brain development[J]. The Journal of Biomedical Research, 2022, 36(4): 242-254. doi: 10.7555/JBR.36.20220074
Citation: Yuanyuan Wang, Liya Liu, Mingyan Lin. Psychiatric risk gene transcription factor 4 preferentially regulates cortical interneuron neurogenesis during early brain development[J]. The Journal of Biomedical Research, 2022, 36(4): 242-254. doi: 10.7555/JBR.36.20220074

Psychiatric risk gene transcription factor 4 preferentially regulates cortical interneuron neurogenesis during early brain development

doi: 10.7555/JBR.36.20220074
More Information
  • Corresponding author: Mingyan Lin, Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, Jiangsu 211166, China. Tel: +86-25-86869432, E-mail: linmingyan@njmu.edu.cn
  • Received: 2022-04-05
  • Revised: 2022-05-31
  • Accepted: 2022-06-01
  • Published: 2022-07-28
  • Issue Date: 2022-07-28
  • Genetic variants within or near the transcription factor 4 gene (TCF4) are robustly implicated in psychiatric disorders including schizophrenia. However, the biological pleiotropy poses considerable obstacles to dissect the potential relationship between TCF4 and those highly heterogeneous diseases. Through integrative transcriptomic analysis, we demonstrated that TCF4 is preferentially expressed in cortical interneurons during early brain development. Therefore, disruptions of interneuron development might be the underlying contribution of TCF4 perturbation to a range of neurodevelopmental disorders. Here, we performed chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 on human medial ganglionic eminence-like organoids (hMGEOs) to identify genome-wide TCF4 binding sites, followed by integration of multi-omics data from human fetal brain. We observed preferential expression of the isoform TCF4-B over TCF4-A. De novo motif analysis found that the identified 5916 TCF4 binding sites are significantly enriched for the E-box sequence. The predicted TCF4 targets in general have positively correlated expression levels with TCF4 in the cortical interneurons, and are primarily involved in biological processes related to neurogenesis. Interestingly, we found that TCF4 interacts with non-bHLH proteins such as FOS/JUN, which may underlie the functional specificity of TCF4 in hMGEOs. This study highlights the regulatory role of TCF4 in interneuron development and provides compelling evidence to support the biological rationale linking TCF4 to the developing cortical interneuron and psychiatric disorders.

     

  • CLC number: R749.4, Document code: A
    The authors reported no conflict of interests.
    ρ These authors contributed equally to this work.
  • loading
  • [1]
    Massari ME, Murre C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms[J]. Mol Cell Biol, 2000, 20(2): 429–440. doi: 10.1128/MCB.20.2.429-440.2000
    [2]
    Jung M, Häberle BM, Tschaikowsky T, et al. Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons[J]. Mol Autism, 2018, 9: 20. doi: 10.1186/s13229-018-0200-1
    [3]
    Kennedy AJ, Rahn EJ, Paulukaitis BS, et al. Tcf4 regulates synaptic plasticity, DNA methylation, and memory function[J]. Cell Rep, 2016, 16(10): 2666–2685. doi: 10.1016/j.celrep.2016.08.004
    [4]
    Teixeira JR, Szeto RA, Carvalho VMA, et al. Transcription factor 4 and its association with psychiatric disorders[J]. Transl Psychiatry, 2021, 11(1): 19. doi: 10.1038/s41398-020-01138-0
    [5]
    Marín O, Rubenstein JLR. A long, remarkable journey: tangential migration in the telencephalon[J]. Nat Rev Neurosci, 2001, 2(11): 780–790. doi: 10.1038/35097509
    [6]
    Mesman S, Bakker R, Smidt MP. Tcf4 is required for correct brain development during embryogenesis[J]. Mol Cell Neurosci, 2020, 106: 103502. doi: 10.1016/j.mcn.2020.103502
    [7]
    Shipley MM, Mangold CA, Szpara ML. Differentiation of the SH-SY5Y human neuroblastoma cell line[J]. J Vis Exp, 2016, (108): 53193. doi: 10.3791/53193
    [8]
    Forrest MP, Hill MJ, Kavanagh DH, et al. The psychiatric risk gene Transcription factor 4 (TCF4) regulates neurodevelopmental pathways associated with schizophrenia, autism, and intellectual disability[J]. Schizophr Bull, 2018, 44(5): 1100–1110. doi: 10.1093/schbul/sbx164
    [9]
    Xia H, Jahr FM, Kim NK, et al. Building a schizophrenia genetic network: transcription factor 4 regulates genes involved in neuronal development and schizophrenia risk[J]. Hum Mol Genet, 2018, 27(18): 3246–3256. doi: 10.1093/hmg/ddy222
    [10]
    Zhong S, Zhang S, Fan X, et al. A single-cell RNA-seq survey of the developmental landscape of the human prefrontal cortex[J]. Nature, 2018, 555(7697): 524–528. doi: 10.1038/nature25980
    [11]
    Fan X, Dong J, Zhong S, et al. Spatial transcriptomic survey of human embryonic cerebral cortex by single-cell RNA-seq analysis[J]. Cell Res, 2018, 28(7): 730–745. doi: 10.1038/s41422-018-0053-3
    [12]
    Liu Y, Liu H, Sauvey C, et al. Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells[J]. Nat Protoc, 2013, 8(9): 1670–1679. doi: 10.1038/nprot.2013.106
    [13]
    Stuart T, Butler A, Hoffman P, et al. Comprehensive integration of single-cell data[J]. Cell, 2019, 177(7): 1888–1902.e21. doi: 10.1016/j.cell.2019.05.031
    [14]
    Landt SG, Marinov GK, Kundaje A, et al. ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia[J]. Genome Res, 2012, 22(9): 1813–1831. doi: 10.1101/gr.136184.111
    [15]
    Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform[J]. Bioinformatics, 2010, 26(5): 589–595. doi: 10.1093/bioinformatics/btp698
    [16]
    Rozowsky J, Euskirchen G, Auerbach RK, et al. PeakSeq enables systematic scoring of ChIP-seq experiments relative to controls[J]. Nat Biotechnol, 2009, 27(1): 66–75. doi: 10.1038/nbt.1518
    [17]
    Ramírez F, Ryan DP, Grüning B, et al. deepTools2: a next generation web server for deep-sequencing data analysis[J]. Nucleic Acids Res, 2016, 44(W1): W160–W165. doi: 10.1093/nar/gkw257
    [18]
    Robinson JT, Thorvaldsdóttir H, Winckler W, et al. Integrative genomics viewer[J]. Nat Biotechnol, 2011, 29(1): 24–26. doi: 10.1038/nbt.1754
    [19]
    Yu G, Wang L, He Q. ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization[J]. Bioinformatics, 2015, 31(14): 2382–2383. doi: 10.1093/bioinformatics/btv145
    [20]
    McLean CY, Bristor D, Hiller M, et al. GREAT improves functional interpretation of cis-regulatory regions[J]. Nat Biotechnol, 2010, 28(5): 495–501. doi: 10.1038/nbt.1630
    [21]
    Heinz S, Benner C, Spann N, et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities[J]. Mol Cell, 2010, 38(4): 576–589. doi: 10.1016/j.molcel.2010.05.004
    [22]
    Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data[J]. Innovation, 2021, 2(3): 100141. doi: 10.1016/j.xinn.2021.100141
    [23]
    Janky R, Verfaillie A, Imrichová H, et al. iRegulon: from a gene list to a gene regulatory network using large motif and track collections[J]. PLoS Comput Biol, 2014, 10(7): e1003731. doi: 10.1371/journal.pcbi.1003731
    [24]
    Bailey TL, Gribskov M. Combining evidence using p-values: application to sequence homology searches[J]. Bioinformatics, 1998, 14(1): 48–54. doi: 10.1093/bioinformatics/14.1.48
    [25]
    Ding J, Hu H, Li X. SIOMICS: a novel approach for systematic identification of motifs in ChIP-seq data[J]. Nucleic Acids Res, 2014, 42(5): e35. doi: 10.1093/nar/gkt1288
    [26]
    Fromer M, Pocklington AJ, Kavanagh DH, et al. De novo mutations in schizophrenia implicate synaptic networks[J]. Nature, 2014, 506(7487): 179–184. doi: 10.1038/nature12929
    [27]
    Xiang Y, Tanaka Y, Patterson B, et al. Fusion of regionally specified hpsc-derived organoids models human brain development and interneuron migration[J]. Cell Stem Cell, 2017, 21(3): 383–398.e7. doi: 10.1016/j.stem.2017.07.007
    [28]
    Yan L, Guo H, Hu B, et al. Epigenomic landscape of human fetal brain, heart, and liver[J]. J Biol Chem, 2016, 291(9): 4386–4398. doi: 10.1074/jbc.M115.672931
    [29]
    Parnavelas JG, Anderson SA, Lavdas AA, et al. The contribution of the ganglionic eminence to the neuronal cell types of the cerebral cortex[J]. Novartis Found Symp, 2000, 228: 129–139. doi: 10.1002/0470846631.ch10
    [30]
    Nakajima K. GABAergic interneuron migration and the evolution of the neocortex[J]. Dev Growth Differ, 2012, 54(3): 366–372. doi: 10.1111/j.1440-169X.2012.01351.x
    [31]
    Tau GZ, Peterson BS. Normal development of brain circuits[J]. Neuropsychopharmacology, 2010, 35(1): 147–168. doi: 10.1038/npp.2009.115
    [32]
    Skene NG, Bryois J, Bakken TE, et al. Genetic identification of brain cell types underlying schizophrenia[J]. Nat Genet, 2018, 50(6): 825–833. doi: 10.1038/s41588-018-0129-5
    [33]
    Birey F, Andersen J, Makinson CD, et al. Assembly of functionally integrated human forebrain spheroids[J]. Nature, 2017, 545(7652): 54–59. doi: 10.1038/nature22330
    [34]
    Sepp M, Kannike K, Eesmaa A, et al. Functional diversity of human basic helix-loop-helix transcription factor tcf4 isoforms generated by alternative 5' exon usage and splicing[J]. PLoS One, 2011, 6(7): e22138. doi: 10.1371/journal.pone.0022138
    [35]
    Gao R, Penzes P. Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders[J]. Curr Mol Med, 2015, 15(2): 146–167. doi: 10.2174/1566524015666150303003028
    [36]
    Wang P, Lin M, Pedrosa E, et al. CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment[J]. Mol Autism, 2015, 6(1): 55. doi: 10.1186/s13229-015-0048-6
    [37]
    Bertrand N, Castro DS, Guillemot F. Proneural genes and the specification of neural cell types[J]. Nat Revs Neurosci, 2002, 3(7): 517–530. doi: 10.1038/nrn874
    [38]
    Chinenov Y, Kerppola TK. Close encounters of many kinds: Fos-Jun interactions that mediate transcription regulatory specificity[J]. Oncogene, 2001, 20(19): 2438–2452. doi: 10.1038/sj.onc.1204385
    [39]
    Wittmann M-T, Katada S, Sock E, et al. scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse[J]. Development, 2021, 148(14): dev196022. doi: 10.1242/dev.196022
  • JBR-2022-0074-supplementary.pdf
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(5)  / Tables(1)

    Article Metrics

    Article views (316) PDF downloads(32) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return