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WDR5 Regulates Left-Right Patterning Via Chromatin-Dependent and -Independent Functions Saurabh S

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WDR5 Regulates Left-Right Patterning Via Chromatin-Dependent and -Independent Functions Saurabh S © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev159889. doi:10.1242/dev.159889 RESEARCH REPORT WDR5 regulates left-right patterning via chromatin-dependent and -independent functions Saurabh S. Kulkarni and Mustafa K. Khokha* ABSTRACT Capdevila et al., 2000; Hamada et al., 2002). However, a Congenital heart disease (CHD) is a major cause of infant mortality mechanism connecting cilia, chromatin modifiers, and CHD/Htx and morbidity, yet the genetic causes and mechanisms remain has not been established. Here, we show that WDR5, a histone opaque. In a patient with CHD and heterotaxy, a disorder of left-right modifier, is necessary for both LR patterning and ciliogenesis. (LR) patterning, a de novo mutation was identified in the chromatin LR patterning is established at a conserved ciliated structure, the ’ modifier gene WDR5. WDR5 acts as a scaffolding protein in the H3K4 LR organizer (LRO) [the node in mouse, Kupffer s vesicle in fish methyltransferase complex, but a role in LR patterning is unknown. and gastrocoel roof plate (GRP) in frogs] (Burdine and Schier, 2000; Here, we show that Wdr5 depletion leads to LR patterning defects in Capdevila et al., 2000; Hamada et al., 2002; Blum et al., 2014). Two Xenopus via its role in ciliogenesis. Unexpectedly, we find a dual role types of monociliated cells populate the LRO: cells in the middle are for WDR5 in LR patterning. First, WDR5 is expressed in the nuclei of enriched in motile cilia that create leftward extracellular fluid flow, monociliated cells of the LR organizer (LRO) and regulates foxj1 which is detected by peripheral cells that have a preponderance of expression. LR defects in wdr5 morphants can be partially rescued immotile sensory cilia (Doerks et al., 2002; Basu and Brueckner, with the addition of foxj1. Second, WDR5 localizes to the bases of 2008; Schweickert et al., 2007; Boskovski et al., 2013). Once flow is dand5 cilia. Using a mutant form of WDR5, we demonstrate that WDR5 also sensed at the LRO left margin, (alternatively referred to as Cerl2 coco Xenopus has an H3K4-independent role in LR patterning. Guided by the patient in mouse and in ; a Nodal antagonist) is pitx2 phenotype, we identify multiple roles for WDR5 in LR patterning, downregulated, leading to upregulation in the left lateral plate providing plausible mechanisms for its role in ciliopathies like mesoderm (Burdine and Schier, 2000; Capdevila et al., 2000; heterotaxy and CHD. Hamada et al., 2002; Blum et al., 2014; Vonica and Brivanlou, 2007). The activation of pitx2 in the lateral plate mesoderm is KEY WORDS: Congenital heart disease, Heterotaxy, Xenopus, H3K4 associated with organ lateralization (Lin et al., 1999). methylation, Cilia WDR5 is a core subunit of the human MLL and SET1 histone H3 Lys4 methyltransferase (H3K4MT) complexes that are essential for INTRODUCTION chromatin modification and transcriptional regulation (Wysocka et al., Congenital heart disease (CHD) is the most common developmental 2005; Couture et al., 2006; Dou et al., 2006; Trievel and Shilatifard, defect (Van der Linde et al., 2011). However, our understanding of 2009; Couture and Skiniotis, 2013; Patel et al., 2008b). In particular, the genetic etiologies of CHD remains poor. A recent genetic H3K4MTs function as a complex consisting of one catalytic subunit analysis of CHD patients identified a marked enrichment in genes [SET1A/B (SETD1A/B) or MLL1-4 (KMT2A-D) proteins] and four involved in chromatin modification, specifically genes involved in core regulatory subunits (WDR5, RbBP5, ASH2L and DPY-30) H3K4/H3K27 methylation or H2BK120 ubiquitination (Zaidi et al., (Trievel and Shilatifard, 2009; Couture and Skiniotis, 2013; Takahashi 2013; Homsy et al., 2015). However, how global regulators of et al., 2011). These regulatory subunits form a subcomplex that binds chromatin states could lead to specific phenotypes, such as CHD, the catalytic subunit and dramatically enhances its H3K4MT activity remains unanswered. To address this question, we began our studies (Patel et al., 2009). Depletion of any of the regulatory subunits impairs with WDR5, a recent candidate gene for CHD and a critical member H3K4 methylation (Steward et al., 2006; Dou et al., 2006; Wysocka of the histone (H3K4) methylation pathway (Zaidi et al., 2013; et al., 2005; Cao et al., 2010). WDR5, a highly conserved scaffolding Wysocka et al., 2005). protein, is essential for the association of RbBP5, ASH2L and DPY- The patient with a de novo missense mutation, K7Q, in WDR5 30 with MLL1 via its β-propeller structure (Odho et al., 2010; Trievel had a conotruncal defect with a right aortic arch (normally the aortic and Shlatifard, 2009; Patel et al., 2008b). The central pocket made by arch is on the left), a mild heterotaxy (Htx) phenotype (Zaidi et al., the sevenfold propeller is crucial for binding H3 and MLL (Song and 2013). Htx results from aberrant left-right (LR) patterning of Kingston, 2008; Patel et al., 2008a; Schuetz et al., 2006; Ruthenburg internal organs and can be associated with a severe form of CHD et al., 2006; Couture et al., 2006). Point mutations, for example, in the (Sutherland and Ware, 2009; Amack and Yost, 2010; Hamada et al., arginine-binding cavity of WDR5 (S91K or F133A), can disrupt the 2002). Cilia are well known to be essential for LR patterning (Li H3K4MT complex (Patel et al., 2008b). Interestingly, the patient et al., 2015; Blum et al., 2014; Basu and Brueckner, 2008; mutation (K7Q) lies outside the β-propeller, in the N-terminal tail (first ∼30 amino acids) that is not required for H3K4MT function (Schuetz et al., 2006), making the disease relevance of this mutation uncertain. Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. RESULTS AND DISCUSSION *Author for correspondence ([email protected]) Wdr5 depletion alters LR patterning in Xenopus tropicalis S.S.K., 0000-0002-0882-6478; M.K.K., 0000-0002-9846-7076 Previously, in a CHD patient with a right (rather than the normally left) aortic arch, a de novo mutation (K7Q) implicated WDR5 as a Received 25 September 2017; Accepted 24 October 2018 candidate disease gene (Zaidi et al., 2013). Therefore, we DEVELOPMENT 1 RESEARCH REPORT Development (2018) 145, dev159889. doi:10.1242/dev.159889 investigated whether WDR5 is essential for LR patterning in We investigated multiple potential reasons for cilia defects. First, Xenopus. Depletion of Wdr5 in Xenopus leads to substantial LRO patterning is dependent on proper dorsoventral (DV) pericardial edema that alters the structure of the heart, precluding patterning, so we began by examining DV markers in gastrula accurate determination of its cardiac looping. Therefore, we (stages 10-11) or postgastrula (stage 14) embryos (Fig. S3A,B) examined global markers of LR patterning: pitx2c and dand5 (Khokha et al., 2005; Heasman, 2006; Niehrs et al., 2001). (Fig. S1). Using a wdr5 morpholino oligonucleotide (MO), Wdr5 Interestingly, following Wdr5 depletion, we detected an increase in knockdown led to abnormal patterns of both pitx2c (∼55%) and expression in dkk1, a known WNT protein antagonist (Glinka et al., dand5 (∼40%) (Fig. 1A,B). To examine the specificity and 1998). Previous studies have shown that the transcriptional efficiency of our Wdr5 depletion, we employed multiple tests. First regulation of some WNT regulators and target genes is dependent by western blotting, we previously showed that Wdr5 protein is on WDR5; thus, expansion of dkk1 in our wdr5 morphants supports reduced in morphants, which is rescued by injecting human wild-type these studies (Zhu et al., 2008; Gori et al., 2006). However, we did (WT) WDR5 mRNA (Kulkarni et al., 2018). In addition, we not observe any change in the expression of other key DV patterning demonstrated that the anti-WDR5 antibody was specific using a serial genes, including foxj1, at gastrula stage. Second, although DV dilution of a blocking peptide that reduced the WDR5 signal on the patterning appears generally normal at the gastrula stages, we western blot (Kulkarni et al., 2018). Second, injection of a scrambled considered the possibility that the LRO itself was mispatterned. MO does not alter pitx2c expression compared with that of uninjected Prior to the onset of cilia-mediated flow (stage 16), dand5 controls (Fig. 1C). Third, we can partially rescue alterations in pitx2c expression is symmetric at the lateral margins, which is expression in Wdr5-depleted embryos by co-injecting WT human unchanged in control or Wdr5-depleted embryos (Fig. S3C,F). WDR5 mRNA tagged with 3xGFP (Fig. 1D). Fourth, the depletion of Further, we checked the expression of xnr1, which is also symmetric Wdr5 using a second ATG MO also led to abnormal patterns of at the lateral margins at these stages. It was also similar between pitx2c (Fig. 1E). Together, we conclude that the Wdr5 depletion by controls and morphants, demonstrating that LRO cell fate MO is specific and is essential for global LR patterning. specification was not drastically affected in morphants (Fig. S3C,F). Disruptions in both dand5 and pitx2c point to a defect in the Mispatterning of the LR axis could also arise from defects in LRO, possibly due to cilia-mediated signaling (Hamada et al., 2002; establishing the midline barrier. Therefore, we checked the Doerks et al., 2002; Schweickert et al., 2007). Previous studies have expression of sonic hedgehog (shh) and lefty at the midline and shown that cilia motility on the left but not on the right side of the found that expression was unaltered between controls and LRO is crucial for proper LR patterning (Vick et al., 2009). Indeed, morphants (Fig. S3D,F). Based on these results, we conclude that left-sided wdr5 knockdown led to a higher percentage of abnormal the LRO in wdr5 morphants is normally patterned overall and expression patterns for both LR markers (dand5 ∼80% and pitx2c sought other explanations for the defects in cilia.
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