Alternative titles; symbols
HGNC Approved Gene Symbol: WDR5
Cytogenetic location: 9q34.2 Genomic coordinates (GRCh38): 9:134,135,199-134,159,968 (from NCBI)
WDR5 is a member of the WD repeat-containing protein family. For background information on this family, see 606045.
By differential display of genes induced in mouse prechondroblastic cells by BMP2 (112261), Gori et al. (2001) cloned mouse Wdr5, which they called Big3. The deduced 328-amino acid protein is composed primarily of 7 WD40 repeats in a beta-propeller structure. Northern blot analysis of several mouse tissues detected highest expression in testis. Wdr5 was also expressed in immortalized murine bone marrow stromal cells, osteoblasts, osteocytes, and growth plate chondrocytes, as well as in primary calvarial osteoblasts. Immunohistochemical analysis of embryonic mouse bone detected Wdr5 in osteoblasts of calvaria.
Gori et al. (2001) found that Wdr5 accelerated the program of osteoblastic differentiation in mouse osteoblastic cells as measured by alkaline phosphatase activity and cyclic AMP production in response to parathyroid hormone (PTH; 168450). The response to PTH was associated with PTH binding. Wdr5 also increased expression of Cbfa1 (600211), type I collagen (see 120150), and osteocalcin (112260) mRNA and accelerated the formation of mineralized nodules in transfected cells.
Brown et al. (2005) identified 2 PER1 (602260)-associated factors, NONO (300084) and WDR5, that modulate PER activity. The reduction of NONO expression by RNA interference (RNAi) attenuated circadian rhythms in mammalian cells, and fruit flies carrying a hypomorphic allele were nearly arrhythmic. WDR5, a subunit of histone methyltransferase complexes, augmented PER-mediated transcriptional repression, and its reduction by RNAi diminished circadian histone methylation at the promoter of a clock gene.
WDR5 is a component of the mammalian SET1A (611052)/SET1B (611055) histone H3-Lys4 methyltransferase complexes (Lee et al., 2007).
By mass spectrometric analysis, Higa et al. (2006) identified over 20 WDR proteins that interacted with the CUL4 (see 603137)-DDB1 (600045)-ROC1 (RBX1; 603814) complex, including WDR5. Sequence alignment revealed that most of the interacting WDR proteins had a centrally positioned WDxR/K submotif. Knockdown studies suggested that the WDR proteins functioned as substrate-specific adaptors. For example, inactivation of L2DTL (DTL; 610617), but not other WDR proteins, prevented CUL4-DDB1-dependent proteolysis of CDT1 (605525) following gamma irradiation. Inactivation of WDR5 or EED (605984), but not other WDR proteins, altered the pattern of CUL4-DDB1-dependent histone H3 (see 602810) methylation.
Zhu et al. (2008) stated that Wdr5 enhances canonical Wnt (see WNT1, 164820) signaling concomitant with differentiation in mouse osteoblasts. They found that reduced endogenous Wdr5 expression via small interfering RNA downregulated Wnt signaling and inhibited osteoblast differentiation. Chromatin immunoprecipitation demonstrated that Wdr5 associated with the Wnt1 promoter and with Wnt response elements of the Myc (190080) and Runx2 (600211) promoters. Wdr5 suppression appeared to interfere with Wnt signaling at multiple stages. Zhu et al. (2008) concluded that optimal Wdr5 levels are required for induction of the osteoblast phenotype.
Using mass spectrometry, Wang et al. (2008) identified WDR5 as a component of the ADA2A (TADA2A; 602276)-containing (ATAC) histone acetyltransferase complex in HeLa cells.
El-Brolosy et al. (2019) analyzed several models of transcriptional adaptation in zebrafish and mouse and uncovered a requirement for mutant mRNA degradation. Alleles that fail to transcribe the mutated gene do not exhibit transcriptional adaptation, and these alleles give rise to more severe phenotypes than alleles displaying mutant mRNA decay. Transcriptome analysis in alleles displaying mutant mRNA decay revealed the upregulation of a substantial proportion of the genes that exhibit sequence similarity with the mutated gene's mRNA, suggesting a sequence-dependent mechanism. In a targeted small interfering RNA (siRNA) screen to identify epigenetic modulators that are involved in transcriptional adaptation, knockdown of the histone lysine demethylases KDM4 (see 609764) or KDM6 (see 300128), which remove the inhibitory histone H3 lys9 trimethylation (H3K9me3) and H3K27me3 marks, respectively, dampened the transcriptional adaptation response. However, the strongest effect was observed after knockdown of WDR5, a member of the COMPASS complex, which generates the permissive histone mark H3K4me3. El-Brolosy et al. (2019) concluded that their data suggested a model in which, concomitant with mutant mRNA degradation, decay factors translocate to the nucleus, where they bind to specific loci (possibly guided by decay intermediates) and recruit histone modifiers and/or chromatin remodellers to upregulate transcription. El-Brolosy et al. (2019) stated that the prevailing hypothesis was that pathogenic missense mutations tend to be more common than nonsense mutations in affected individuals because they might lead to constitutively active or dominant-negative proteins. However, El-Brolosy et al. (2019) proposed that nonsense mutations are less common because they might result in mRNA decay-triggered upregulation of related genes and therefore not cause noticeable symptoms. The authors suggested that detailed transcriptomic analyses of relevant individuals will help to test this hypothesis.
Ma et al. (2019) used zebrafish knockdown and knockout models of capn3a (see 114240) and nid1a (see 131390) genes to show that mRNA bearing a premature termination codon (PTC) promptly triggers a genetic compensation response (GCR) that involves Upf3a (605530) and components of the COMPASS complex. Unlike capn3a-knockdown embryos, which have small livers, and nid1a-knockdown embryos, which have short body lengths, capn3a-null and nid1a-null mutants appear normal. These phenotypic differences have been attributed to the upregulation of other genes in the same families. By analyzing 6 uniquely designed transgenes, Ma et al. (2019) demonstrated that the GCR is dependent on both the presence of a PTC and the nucleotide sequence of the transgene mRNA, which is homologous to the compensatory endogenous genes. Ma et al. (2019) showed that upf3a and components of the COMPASS complex, including wdr5, function in GCR, and demonstrated that the GCR is accompanied by an enhancement of H3K4me3 at the transcription start site regions of the compensatory genes. Ma et al. (2019) concluded that their findings provided a potential mechanistic basis for the GCR, and suggested that they may help lead to the development of therapeutic strategies that treat missense mutations associated with genetic disorders by either creating a PTC in the mutated gene or introducing a transgene containing a PTC to trigger a GCR.
In an accompanying commentary, Wilkinson (2019) termed the upregulatory response observed by El-Brolosy et al. (2019) and Ma et al. (2019) 'nonsense-induced transcriptional compensation' (NITC).
The International Radiation Hybrid Mapping Consortium mapped the WDR5 gene to chromosome 9 (RH98879).
Brown, S. A., Ripperger, J., Kadener, S., Fleury-Olela, F., Vilbois, F., Rosbach, M., Schibler, U. PERIOD1-associated proteins modulate the negative limb of the mammalian circadian oscillator. Science 308: 693-696, 2005. [PubMed: 15860628] [Full Text: https://doi.org/10.1126/science.1107373]
El-Brolosy, M. A., Kontarakis, Z., Rossi, A., Kuenne, C., Gunther, S., Fukuda, N., Kikhi, K., Boezio, G. L. M., Takacs, C. M., Lai, S.-L., Fukuda, R., Gerri, C., Giraldez, A. J., Stainier, D. Y. R. Genetic compensation triggered by mutant mRNA degradation. Nature 568: 193-197, 2019. [PubMed: 30944477] [Full Text: https://doi.org/10.1038/s41586-019-1064-z]
Gori, F., Divieti, P., Demay, M. B. Cloning and characterization of a novel WD-40 repeat protein that dramatically accelerates osteoblastic differentiation. J. Biol. Chem. 276: 46515-46522, 2001. [PubMed: 11551928] [Full Text: https://doi.org/10.1074/jbc.M105757200]
Higa, L. A., Wu, M., Ye, T., Kobayashi, R., Sun, H., Zhang, H. CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nature Cell Biol. 8: 1277-1283, 2006. [PubMed: 17041588] [Full Text: https://doi.org/10.1038/ncb1490]
Lee, J. H., Tate, C. M., You, J. S., Skalnik, D. G. Identification and characterization of the human Set1B histone H3-Lys4 methyltransferase complex. J. Biol. Chem. 282: 13419-13428, 2007. [PubMed: 17355966] [Full Text: https://doi.org/10.1074/jbc.M609809200]
Ma, Z., Zhu, P., Shi, H., Guo, L., Zhang, Q., Chen, Y., Chen, S., Zhang, Z., Peng, J., Chen, J. PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASS components. Nature 568: 259-263, 2019. [PubMed: 30944473] [Full Text: https://doi.org/10.1038/s41586-019-1057-y]
Wang, Y.-L., Faiola, F., Xu, M., Pan, S., Martinez, E. Human ATAC is a GCN5/PCAF-containing acetylase complex with a novel NC2-like histone fold module that interacts with the TATA-binding protein. J. Biol. Chem. 283: 33808-33815, 2008. [PubMed: 18838386] [Full Text: https://doi.org/10.1074/jbc.M806936200]
Wilkinson, M. F. Genetic paradox explained by nonsense. Nature 568: 179-180, 2019. [PubMed: 30962551] [Full Text: https://doi.org/10.1038/d41586-019-00823-5]
Zhu, E. D., Demay, M. B., Gori, F. Wdr5 is essential for osteoblast differentiation. J. Biol. Chem. 283: 7361-7367, 2008. [PubMed: 18201971] [Full Text: https://doi.org/10.1074/jbc.M703304200]