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Proc Natl Acad Sci U S A January 1, 2019; 116 (28): 14049-14054.
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Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility.

Robson A , Makova SZ , Barish S , Zaidi S , Mehta S , Drozd J , Jin SC , Gelb BD , Seidman CE , Chung WK , Lifton RP , Khokha MK , Brueckner M .

Genomic analyses of patients with congenital heart disease (CHD) have identified significant contribution from mutations affecting cilia genes and chromatin remodeling genes; however, the mechanism(s) connecting chromatin remodeling to CHD is unknown. Histone H2B monoubiquitination (H2Bub1) is catalyzed by the RNF20 complex consisting of RNF20, RNF40, and UBE2B. Here, we show significant enrichment of loss-of-function mutations affecting H2Bub1 in CHD patients (enrichment 6.01, P = 1.67 × 10-03), some of whom had abnormal laterality associated with ciliary dysfunction. In Xenopus, knockdown of rnf20 and rnf40 results in abnormal heart looping, defective development of left-right (LR) asymmetry, and impaired cilia motility. Rnf20, Rnf40, and Ube2b affect LR patterning and cilia synergistically. Examination of global H2Bub1 level in Xenopus embryos shows that H2Bub1 is developmentally regulated and requires Rnf20. To examine gene-specific H2Bub1, we performed ChIP-seq of mouse ciliated and nonciliated tissues and showed tissue-specific H2Bub1 marks significantly enriched at cilia genes including the transcription factor Rfx3 Rnf20 knockdown results in decreased levels of rfx3 mRNA in Xenopus, and exogenous rfx3 can rescue the Rnf20 depletion phenotype. These data suggest that Rnf20 functions at the Rfx3 locus regulating cilia motility and cardiac situs and identify H2Bub1 as an upstream transcriptional regulator controlling tissue-specific expression of cilia genes. Our findings mechanistically link the two functional gene ontologies that have been implicated in human CHD: chromatin remodeling and cilia function.

PubMed ID: 31235600
PMC ID: PMC6628794
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus
Genes referenced: arl13b ccdc88a chrd.1 cplane1 ctrl dand5 dnah11 dnah7 dnah9 foxj1 h2bc21 hk1 kidins220 kif3a lhx6 nodal npat pitx2 psmd6 rfx3 rnf20 rnf40 rpl8 sgce spata6l ube2b
Morpholinos: rnf20 MO1 rnf40 MO1 ube2b MO1
gRNAs referenced: rnf20 gRNA1

GEO Series: GSE132116: NCBI
GSE132117: NCBI

Article Images: [+] show captions
References [+] :
Afzelius, A human syndrome caused by immotile cilia. 1976, Pubmed