Coevolution of the CDCA7-HELLS ICF-related nucleosome remodeling complex and DNA methyltransferases

Abstract

5-Methylcytosine (5mC) and DNA methyltransferases (DNMTs) are broadly conserved in eukaryotes but are also frequently lost during evolution. The mammalian SNF2 family ATPase HELLS and its plant ortholog DDM1 are critical for the maintenance of 5mC. Mutations in HELLS, its activator subunit CDCA7, and the de novo DNA methyltransferase DNMT3B, cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, a genetic disorder associated with the loss of DNA methylation. We here examine the coevolution of CDCA7, HELLS and DNMTs. While DNMT3, the maintenance DNA methyltransferase (DNMT1), HELLS, and CDCA7 are all highly conserved in vertebrates and green plants, they are frequently lost in other evolutionary clades. The presence-absence patterns of these genes are not random; almost all CDCA7 harboring eukaryote species also have HELLS and DNMT1 (or another maintenance methyltransferase, DNMT5), whereas species that maintain DNMT1 or HELLS without CDCA7 are identified in several clades, such as Fungi and Ecdysozoa. Coevolution of presence-absence patterns (CoPAP) analysis in Ecdysozoa further indicates coevolutionary linkages among CDCA7, HELLS, DNMT1 and its activator UHRF1. Our study suggests that a unique specialized role of CDCA7 in HELLS-dependent DNA methylation maintenance is broadly inherited from the last eukaryotic common ancestor.

CDCA7 is a hemimethylated DNA adaptor for the nucleosome remodeler HELLS

“…Although CDCA7 coevolved with HELLS and the maintenance DNA methyltransferases ( 28 ), their mechanistic link remained unclear. The first hint emerged when we observed that HELLS preferentially accumulated on sperm chromatin after incubation in interphase DNMT1-depleted Xenopus egg extracts (ΔDNMT1) (Fig.…”

“…The importance of HELLS and its plant ortholog DDM1 in DNA methylation has been established in vertebrates and in plants ( 18–25 ), and it has been suggested that the nucleosome remodeling activity of HELLS/DDM1 facilitates DNA methylation ( 26, 27 ). However, it remains unclear why a role in promoting DNA methylation is uniquely carried out by HELLS/DDM1 among several other coexisting SNF2-family ATPases with similar nucleosome remodeling activity, such as SNF2 (SMARCA2/4), INO80, and ISWI (SMARCA1/5) ( 28 ).…”

“…CDCA7 is characterized by its unique zinc-finger domain zf-4CXXC_R1, which is broadly conserved in eukaryotes ( 28 ) (fig. S1).…”

“…CDCA7 homologs with the prototypical zf-4CXXC_R1 domain, containing eleven highly conserved signature cysteine residues and three ICF disease-associated residues, are almost exclusively identified in species that also harbor HELLS/DDM1 and maintenance DNA methyltransferases (DNMT1/MET1 or DNMT5), whereas CDCA7 is almost always lost in species that lack detectable genomic 5mC, such as Drosophila , Tribolium , Microplitis , Caenorhabditis , Schizosaccharomyces , and Saccharomyces ( 28 ). This coevolution analysis suggests that zf-4CXXC_R1 domain became readily dispensable in species that lack methylated DNA ( 28 ). However, the function of zf-4CXXC_R1 remains to be defined.…”

CDCA7-associated global aberrant DNA hypomethylation translates to localized, tissue-specific transcriptional responses

“…A recent evolutionary analysis could trace back CDCA7 and HELLS to the last eukaryotic common ancestor (62), suggesting conserved functions in DNA methylation pathways. We find that CDCA7 predominantly targets the B genomic compartment (Fig.…”