Researchers from Rockefeller University, in collaboration with researchers from the University of Tokyo and Yokohama City University, have identified CDCA7 as a second sensor of hemimethylation in eukaryotes, challenging the long-held belief that UHRF1 was the sole protein responsible for this task.
DNA methylation acts as an epigenetic switch, regulating gene expression without altering the DNA sequence. This process ensures that cells maintain their specific functions, such as preventing brain-related genes from activating in heart cells. However, maintaining accurate DNA methylation patterns is challenging, and disruptions can lead to various diseases, including the rare immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome.
The study, published in Science Advances, reveals that CDCA7 forms a complex with HELLS, a nucleosome remodeler. This complex plays a crucial role in overcoming the barrier of compacted heterochromatin, making DNA accessible for methylation maintenance. CDCA7 recognizes hemimethylated DNA within chromatin and recruits HELLS, which then exposes the hemimethylation site to UHRF1.
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"It's quite an incredible finding," says co-first author Isabel Wassing. "Learning that CDCA7 also acts as a sensor explains why its mutation leads to diseases like ICF syndrome and fills in a major gap in the field of epigenetics."
This discovery provides insight into why cells need two different hemimethylation sensors. CDCA7 appears to be more adept at detecting hemimethylation within dense heterochromatin than UHRF1, ensuring accurate inheritance of DNA methylation patterns during cell division.
The research not only enhances our understanding of epigenetic regulation but also sheds light on the mechanisms underlying diseases caused by dysfunctional methylation. Future studies may explore additional functions of hemimethylation sensors beyond DNA methylation maintenance, potentially uncovering broader roles in gene regulation and chromosome organization.