Dual genomic localizations and gene regulatory functions of MBD-2 with and without NuRD in Caenorhabditis elegans which lacks DNA methylation

5-methylcytosine (5mC) DNA methylation is an ancient epigenetic mechanism. Methyl-CpG-binding domain protein 2 or 3 (MBD2/3) is a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, essential for gene regulation in mammals. The MBD2/3 ortholog is surprisingly preserved even in 5mC-free invertebrates, such as nematodes and flies. We found that Caenorhabditis elegans MBD-2 (Cel-MBD-2), despite without the MBD domain, is a conserved component of the NuRD complex. Cel-MBD-2 null mutation or deletion of its NuRD-interacting coiled-coil domain causes morphological defects and infertility. While a minority of Cel-MBD-2 colocalizes with NuRD at active chromatin, the majority of Cel-MBD-2 localizes to repressive chromatin environments enriched with H3K27me3 and H3K9me2/3, not overlapping with NuRD. The mechanism by which Cel-MBD-2 localizes to the repressive chromatin is still unknown, but is independent of NuRD or MBD-5mC interaction. The potential compensation of DNA methylation by histone modifications highlights the adaptability of epigenetic regulation during evolution. C. elegans has lost DNA methylation and the methyl-binding domain in MBD-2 reader. The authors show that Cel-MBD-2 is a conserved NuRD component. Cel-MBD-2 can either localize to open chromatin with NuRD, or to repressive histone marks without NuRD.