Alternative titles; symbols
HGNC Approved Gene Symbol: TAF4
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38) : 20:61,974,798-62,065,881 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.33 | Intellectual developmental disorder, autosomal dominant 73 | 620450 | Autosomal dominant | 3 |
TAF4 is a core subunit of TFIID, a multiprotein complex and a transcription factor required for the formation of the RNA polymerase II (Pol II) preinitiation complex (PIC). As a TFIID subunit, TAF4 is essential for embryogenesis and embryonic stem cell differentiation (Langer et al., 2016).
Transcription factor TFIID is a multiprotein complex composed of the TATA box-binding protein (TBP; 600075) and multiple TBP-associated factors (TAFs; see 313650). Tanese et al. (1996) cloned cDNAs encoding 2 subunits of the human TFIID complex: TAFII130 (also symbolized TAF2C1) and TAFII100 (TAF2D; 601787). The longest partial cDNA representing human TAFII130 encodes the predicted C-terminal 947 amino acids of the protein and 1.4 kb of 3-prime untranslated sequence; this cDNA appeared to be missing approximately 100 N-terminal amino acids of TAFII130. Tanese et al. (1996) showed that recombinant TAFII100 and TAFII130 associated with endogenous TAFs and TBP to form a TFIID complex in transfected 293 cells. Their experiments also suggested a role for TAFII130 as a direct coactivator target for Sp1 (189906). See also TAF2C2 (601689).
By biochemical purification and genomic screening, Mengus et al. (1997) obtained a full-length cDNA encoding TAF2C1. Sequence analysis predicted that the 1,083-amino acid protein contains a C-terminal domain and a central region highly homologous to those of TAF2C2. TAF2C1 expression was found to enhance transactivation by the class II nuclear receptors RAR (see 180240), THRA (see 190120), and VDR (601769) through activation function-2 in the C-terminal ligand-binding domain.
By in situ hybridization, Langer et al. (2016) showed ubiquitous expression of Taf4a during mouse embryonic development. Taf4a expression overlapped with embryonic expression of Taf4b (601689), suggesting a possible functional redundancy between the 2 genes.
Janssen et al. (2022) stated that the TAF4 gene contains 15 exons.
Stumpf (2024) mapped the TAF4 gene to chromosome 20q13.33 based on an alignment of the TAF4 sequence (GenBank BC167776) with the genomic sequence (GRCh38).
At least 8 neurodegenerative disorders are due to expansions of CAG repeats encoding polyglutamine (polyQ) stretches. These disorders include Huntington disease (143100) and several forms of spinocerebellar ataxia. In connection with the molecular mechanisms of neurodegeneration in these disorders, Shimohata et al. (2000) found that expanded polyQ stretches preferentially bind to TAFII130, which is involved as a coactivator in cAMP-responsive element-binding protein (CREB; 123810)-dependent transcriptional activation; the binding results in strong suppression of CREB-dependent transcriptional activation. This suppression and the cell death induced by polyQ stretches were restored by the coexpression of TAFII130. The results indicated that interference of transcription by the binding of TAFII130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.
Dunah et al. (2002) reported that huntingtin (HTT: 613004) interacts with the transcriptional activator SP1 (189906) and coactivator TAFII130. Coexpression of SP1 and TAFII130 in cultured striatal cells from wildtype and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibited SP1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients.
Zhang et al. (2003) demonstrated that ZBP89 (ZNF148; 601897) repressed SP1-mediated activation of the vimentin (193060) promoter. Coexpression of TAFII130 with ZNF148 and SP1 in insect cells rescued expression. Since both ZNF148 and TAFII130 interacted with a glutamine-rich region of SP1, Zhang et al. (2003) hypothesized that these proteins may compete for SP1 binding.
Cryoelectron Microscopy
Bieniossek et al. (2013) presented the structure of the human core-TFIID complex, consisting of 2 copies each of TAF4, TAF5 (601787), TAF6 (602955), TAF9 (600822), and TAF12 (600773), determined by cryoelectron microscopy at 11.6-angstrom resolution. The structure revealed a 2-fold symmetric, interlaced architecture, with pronounced protrusions, that accommodates all conserved structural features of the TAFs including the histone folds. Bieniossek et al. (2013) further demonstrated that binding of 1 TAF8 (609514)-TAF10 (600475) complex breaks the original symmetry of the core-TFIID. Bieniossek et al. (2013) proposed that the resulting asymmetric structure serves as a functional scaffold to nucleate holo-TFIID assembly, by accreting 1 copy each of the remaining TAFs and TBP.
In 2 unrelated patients with autosomal dominant intellectual developmental disorder-73 (MRD73; 620450), Bertoli-Avella et al. (2021) identified 2 different de novo heterozygous putative loss-of-function mutations in the TAF4 gene (see, e.g., Q949X, 601796.0001). Functional studies of the variants and studies of patient cells were not performed, but the authors postulated haploinsufficiency as the pathogenetic mechanism. The patients were ascertained from a data repository cohort of over 33,000 patients who underwent exome or genome sequencing.
In 8 unrelated patients with MRD73, Janssen et al. (2022) identified de novo heterozygous putative loss-of-function mutations in the TAF4 gene (see, e.g., 601796.0002-601796.0005). The patients were ascertained through the GeneMatcher program. The mutations, which were found by trio whole-exome or trio whole-genome sequencing, were not present in the gnomAD database. Functional studies of the variants were not performed, but all were predicted to result in a loss of function.
Langer et al. (2016) found that Taf4a -/- mouse embryos were present in approximate mendelian ratios until embryonic day (E) 9.5, but they exhibited severe growth retardation due to increased apoptosis and underwent lethality after E9.5. Taf4a -/- embryos also displayed defective heart formation, abnormal anterior patterning, and reduced neural crest domain. Taf4 was dispensable for primordial germ cell (PGC) generation, as PGC specification took place in the absence of Taf4a, but PGCs could not migrate and pursue their proliferation due to the absence of the hindgut. Taf4a -/- embryonic stem cells (ESCs) were viable and displayed integration of Taf4b in TFIID. ESCs lacking either Taf4a or Taf4b were viable, but lack of both proteins resulted in a loss of viability, confirming that Taf4a and Taf4b were redundant in terms of assuring the viability of ESCs. Taf4a -/- ESCs displayed defective neuronal differentiation and adopted a unique state with partially induced expression of differentiation genes and partially repressed expression of pluripotency genes. Further analysis of Taf4a -/- ESCs demonstrated that Taf4 was required for formation of PIC at neuronal genes and was essential for contractile cardiomyocyte differentiation.
In a patient with autosomal dominant intellectual developmental disorder-73 (MRD73; 620450), Bertoli-Avella et al. (2021) identified a de novo heterozygous c.2845C-T transition (c.2845C-T, NM_003185.3) in the TAF4 gene, resulting in a gln949-to-ter (Q949X) substitution. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated haploinsufficiency as the pathogenetic mechanism. The patient was ascertained from a data repository cohort of over 33,000 patients who underwent exome or genome sequencing.
In a 14-year-old boy (P1) with autosomal dominant intellectual developmental disorder-73 (MRD73; 620450), Janssen et al. (2022) identified a de novo heterozygous c.1348C-T transition (c.1348C-T, NM_003185.3) in exon 1 of the TAF4 gene, resulting in a gln450-to-ter (Q450X) substitution. The mutation, which was found by trio whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In an 8-year-old girl (P3) with autosomal dominant intellectual developmental disorder-73 (MRD73; 620450), Janssen et al. (2022) identified a de novo heterozygous c.2185C-T transition (c.2185C-T, NM_003185.3) in exon 7 of the TAF4 gene, resulting in a gln729-to-ter (Q729X) substitution. The mutation, which was found by trio whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In a 3-year-old girl (P4) with autosomal dominant intellectual developmental disorder-73 (MRD73; 620450), Janssen et al. (2022) identified a de novo heterozygous 1-bp duplication (c.2453dup, NM_003185.3) in exon 9 of the TAF4 gene, predicted to result in a frameshift and premature termination (Asn818LysfsTer2). The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In a 16-year-old girl (P6) with autosomal dominant intellectual developmental disorder-73 (MRD73; 620450), Janssen et al. (2022) identified a de novo heterozygous 1-bp deletion (c.2664delA, NM_003185.3) in exon 11 of the TAF4 gene, predicted to result in a frameshift and premature termination (Lys888AsnfsTer4). The mutation, which was found by trio whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
Bertoli-Avella, A. M., Kandaswamy, K. K., Khan, S., Ordonez-Herrera, N., Tripolszki, K., Beetz, C., Rocha, M. E., Urzi, A., Hotakainen, R., Leubauer, A., Al-Ali, R., Karageorgou, V., and 25 others. Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders. Genet. Med. 23: 1551-1568, 2021. [PubMed: 33875846] [Full Text: https://doi.org/10.1038/s41436-021-01159-0]
Bieniossek, C., Papai, G., Schaffitzel, C., Garzoni, F., Chaillet, M., Scheer, E., Papadopoulos, P., Tora, L., Schultz, P., Berger, I. The architecture of human general transcription factor TFIID core complex. Nature 493: 699-702, 2013. [PubMed: 23292512] [Full Text: https://doi.org/10.1038/nature11791]
Dunah, A. W., Jeong, H., Griffin, A., Kim, Y.-M., Standaert, D. G., Hersch, S. M., Mouradian, M. M., Young, A. B., Tanese, N., Krainc, D. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 296: 2238-2243, 2002. [PubMed: 11988536] [Full Text: https://doi.org/10.1126/science.1072613]
Janssen, B. D. E., van den Boogaard, M. H., Lichtenbelt, K., Seaby, E. G., Stals, K., Ellard, S., Newbury-Ecob, R., Dixit, A., Roht, L., Pajusalu, S., Ounap, K., Firth, H. V., and 9 others. De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder. Hum. Mutat. 43: 1844-1851, 2022. [PubMed: 35904126] [Full Text: https://doi.org/10.1002/humu.24444]
Langer, D., Martianov, I., Alpern, D., Rhinn, M., Keime, C., Dolle, P., Mengus, G., Davidson, I. Essential role of the TFIID subunit TAF4 in murine embryogenesis and embryonic stem cell differentiation. Nature Commun. 7: 11063, 2016. [PubMed: 27026076] [Full Text: https://doi.org/10.1038/ncomms11063]
Mengus, G., May, M., Carre, L., Chambon, P., Davidson, I. Human TAF(II)135 potentiates transcriptional activation by the AF-2s of the retinoic acid, vitamin D3, and thyroid hormone receptors in mammalian cells. Genes Dev. 11: 1381-1395, 1997. [PubMed: 9192867] [Full Text: https://doi.org/10.1101/gad.11.11.1381]
Shimohata, T., Nakajima, T., Yamada, M., Uchida, C., Onodera, O., Naruse, S., Kimura, T., Koide, R., Nozaki, K., Sano, Y., Ishiguro, H., Sakoe, K., and 16 others. Expanded polyglutamine stretches interact with TAF(II)130, interfering with CREB-dependent transcription. Nature Genet. 26: 29-36, 2000. [PubMed: 10973244] [Full Text: https://doi.org/10.1038/79139]
Stumpf, A. M. Personal Communication. Baltimore, Md. 06/18/2024.
Tanese, N., Saluja, D., Vassallo, M. F., Chen, J.-L., Admon, A. Molecular cloning and analysis of two subunits of the human TFIID complex: hTAFII130 and hTAFII100. Proc. Nat. Acad. Sci. 93: 13611-13616, 1996. [PubMed: 8942982] [Full Text: https://doi.org/10.1073/pnas.93.24.13611]
Zhang, X., Diab, I. H., Zehner, Z. E. ZBP-89 represses vimentin gene transcription by interacting with the transcriptional activator, Sp1. Nucleic Acids Res. 31: 2900-2914, 2003. [PubMed: 12771217] [Full Text: https://doi.org/10.1093/nar/gkg380]