The WHHERE coactivator complex is required for retinoic acid-dependent regulation of embryonic symmetry

Abstract

Bilateral symmetry is a striking feature of the vertebrate body plan organization. Vertebral precursors, called somites, provide one of the best illustrations of embryonic symmetry. Maintenance of somitogenesis symmetry requires retinoic acid (RA) and its coactivator Rere/Atrophin2. Here, using a proteomic approach we identify a protein complex, containing Wdr5, Hdac1, Hdac2 and Rere (named WHHERE), which regulates RA signaling and controls embryonic symmetry. We demonstrate that Wdr5, Hdac1, and Hdac2 are required for RA signaling in vitro and in vivo. Mouse mutants for Wdr5 and Hdac1 exhibit asymmetrical somite formation characteristic of RA-deficiency. We also identify the Rere-binding histone methyltransferase Ehmt2/G9a, as a RA coactivator controlling somite symmetry. Upon RA treatment, WHHERE and Ehmt2 become enriched at RA target genes to promote RNA polymerase II recruitment. Our work identifies a protein complex linking key epigenetic regulators acting in the molecular control of embryonic bilateral symmetry.

Genotype-phenotype correlations in individuals with pathogenicREREvariants

“…The overlapping phenotypes seen in individuals with deficiency of RERE and CHD7 suggest that they may regulate the expression of a common set of genes in the developing embryo or that their gene targets may function in the same molecular pathways. In support of this hypothesis, we note that RERE has been show to positively regulate retinoic acid signaling during embryonic development (Kumar & Duester, 2014;Vilhais-Neto et al, 2010;Vilhais-Neto et al, 2017). Although, CHD7 has not been shown to regulate retinoic acid signaling, modulation of retinoic acid signaling has been shown to prevent in vivo inner ear and in vitro neural stem cell defects caused by CHD7 deficiency (Micucci et al, 2014).…”

“…Wang, Charroux, Kerridge, & Tsai, 2008;Zoltewicz et al, 2004). One of RERE's roles is to positively regulate retinoic acid signaling in multiple tissues during embryonic development (Kumar & Duester, 2014;Vilhais-Neto et al, 2010;Vilhais-Neto et al, 2017).…”

Making and breaking symmetry in development, growth and disease

“…Biochemical analysis of RA signaling in this context demonstrates that a complex called WHHERE, which consists of WDR5, the histone deacetylases HDAC1 and HDAC2, and the atrophin family protein RERE, positively regulates RA signaling during the control of somite symmetry (Vilhais-Neto et al, 2017, 2010. As such, mutations in Wdr5, Hdac1, Rere and Ehmt2, a gene encoding a histone methyltransferase that can also interact with RERE but more transiently than other members of the WHHERE complex, all cause right-biased somitogenesis delays in the mouse (Vilhais-Neto et al, 2017). Importantly, defective RA signaling does not impact the L-R pathway in the LPM (Niederreither et al, 2001).…”

Rere-dependent Retinoic Acid signaling controls brain asymmetry and handedness

“…The LR symmetry of somite formation is controlled by a bilaterally symmetrical gradient of Fibroblast Growth Factor (FGF) signaling peaking in the posterior PSM 1,2 . This FGF gradient is antagonized by RA signaling produced by the forming somites anteriorly 3–4 . Strikingly, in RA-deficient mice lacking the RA biosynthetic enzyme Raldh2, the Fgf8 gradient in the PSM becomes asymmetric, resulting in a delay of somitogenesis in the right side 5–6 .…”

“…The RA pathway involved in the control of somite symmetry requires the Rere chromatin-remodeling protein which together with Hdac1/2 and Wdr5, forms a coactivator complex called WHHERE 4 . In zebrafish embryos homozygous mutant for the Rere homolog rerea, babyface ( bab tb210 / bab tb210 ), normal somite symmetry was observed, possibly reflecting compensation by a maternal pool of rerea mRNA (Supplementary Table 3) 21 .…”