TAF1 , associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish

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Abstract

The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1’s molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c.3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.

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High-throughput gene targeting and phenotyping in zebrafish using CRISPR/Cas9

Gaurav Varshney, Wuhong Pei, Matthew LaFave … (2015)

The use of CRISPR/Cas9 as a genome-editing tool in various model organisms has radically changed targeted mutagenesis. Here, we present a high-throughput targeted mutagenesis pipeline using CRISPR/Cas9 technology in zebrafish that will make possible both saturation mutagenesis of the genome and large-scale phenotyping efforts. We describe a cloning-free single-guide RNA (sgRNA) synthesis, coupled with streamlined mutant identification methods utilizing fluorescent PCR and multiplexed, high-throughput sequencing. We report germline transmission data from 162 loci targeting 83 genes in the zebrafish genome, in which we obtained a 99% success rate for generating mutations and an average germline transmission rate of 28%. We verified 678 unique alleles from 58 genes by high-throughput sequencing. We demonstrate that our method can be used for efficient multiplexed gene targeting. We also demonstrate that phenotyping can be done in the F 1 generation by inbreeding two injected founder fish, significantly reducing animal husbandry and time. This study compares germline transmission data from CRISPR/Cas9 with those of TALENs and ZFNs and shows that efficiency of CRISPR/Cas9 is sixfold more efficient than other techniques. We show that the majority of published “rules” for efficient sgRNA design do not effectively predict germline transmission rates in zebrafish, with the exception of a GG or GA dinucleotide genomic match at the 5′ end of the sgRNA. Finally, we show that predicted off-target mutagenesis is of low concern for in vivo genetic studies.

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Structure and function of a human TAFII250 double bromodomain module.

R Tjian, Elliott Jacobson, Andreas Ladurner … (2000)

TFIID is a large multiprotein complex that initiates assembly of the transcription machinery. It is unclear how TFIID recognizes promoters in vivo when templates are nucleosome-bound. Here, it is shown that TAFII250, the largest subunit of TFIID, contains two tandem bromodomain modules that bind selectively to multiply acetylated histone H4 peptides. The 2.1 angstrom crystal structure of the double bromodomain reveals two side-by-side, four-helix bundles with a highly polarized surface charge distribution. Each bundle contains an Nepsilon-acetyllysine binding pocket at its center, which results in a structure ideally suited for recognition of diacetylated histone H4 tails. Thus, TFIID may be targeted to specific chromatin-bound promoters and may play a role in chromatin recognition.

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X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

H. Hu, S A Haas, J Chelly … (2015)

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4 −/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

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Author and article information

Contributors

Sanna Gudmundsson:

ORCID: http://orcid.org/0000-0002-2332-074X

sanna.gudmundsson@igp.uu.se

Göran Annerén: goran.anneren@igp.uu.se

Marie-Louise Bondeson: marielouise.bondeson@igp.uu.se

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 24 July 2019

Publication date PMC-release: 24 July 2019

Publication date Collection: 2019

Volume: 9

Electronic Location Identifier: 10730

Affiliations

[1 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Immunology, Genetics and Pathology, , Uppsala University, Science for Life Laboratory, ; Uppsala, 751 08 Sweden

[2 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Organismal Biology, Genome Engineering Zebrafish, Science for Life Laboratory, , Uppsala University, ; Uppsala, 752 36 Sweden

[3 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Information Technology, , Uppsala University, Sweden and Science for Life Laboratory, ; Uppsala, 751 05 Sweden

[4 ]ISNI 0000 0004 0584 1036, GRID grid.413653.6, Department of Paediatrics, , Central Hospital, ; Västerås, 721 89 Sweden

[5 ]ISNI 0000 0000 9071 0620, GRID grid.419538.2, Research Group Development and Disease, , Max Planck Institute for Molecular Genetics, ; Berlin, 141 95 Germany

Author information

Sanna Gudmundsson http://orcid.org/0000-0002-2332-074X

Josefin Johansson http://orcid.org/0000-0002-5152-4096

Vera M. Kalscheuer http://orcid.org/0000-0001-6898-3259

Article

Publisher ID: 46632

DOI: 10.1038/s41598-019-46632-8

PMC ID: 6656882

PubMed ID: 31341187

SO-VID: 68d6d731-2020-4d1f-9f1b-2d79b8dfe930

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 27 September 2018

Date accepted : 1 July 2019

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ScienceOpen disciplines: Uncategorized

Keywords: embryogenesis,gene expression,rna sequencing,genetics research,neurodevelopmental disorders

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ScienceOpen disciplines: Uncategorized

Keywords: embryogenesis, gene expression, rna sequencing, genetics research, neurodevelopmental disorders

TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish

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Most cited references 38

High-throughput gene targeting and phenotyping in zebrafish using CRISPR/Cas9

Structure and function of a human TAFII250 double bromodomain module.

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

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