Revealing the Broad Impact of ORC2 on Human Gene Regulation

Recent research published in Cell Reports has uncovered an unexpectedly extensive role for the Origin Recognition Complex 2 (ORC2) in regulating human gene expression and chromatin structure. Traditionally known as essential for DNA replication initiation in yeast, ORC has now been shown to influence gene activity and epigenetic states in human cells.

Led by Anindya Dutta, Ph.D., from the University of Alabama at Birmingham, the study provides the first detailed exploration of how ORC, especially its ORC2 subunit, interacts with the human genome beyond replication origins. The team employed human cancer cell lines with targeted knockdowns of ORC subunits, revealing that individual ORC subunits bind distinct DNA sites across the genome. Interestingly, these sites are functionally significant, affecting gene expression independently.

In some regions, ORC2 binding facilitated chromatin compaction and repressive histone modifications, reducing gene accessibility. Conversely, in other locations, ORC2 activation promoted an open chromatin state conducive to gene expression. Moreover, ORC2 influences the binding of CTCF, a key protein involved in DNA loop formation and genome organization. Specifically, ORC2 appears to prevent CTCF from binding at certain sites, thereby affecting the formation of chromatin loops that regulate gene activity.

The absence of ORC2 at specific loci led to increased looping, which disrupted enhancer-promoter interactions, depressed gene expression, and facilitated the spread of repressive epigenetic marks. Despite the knockdowns, the mutant cells continued to proliferate and replicate DNA, indicating that ORC's role extends significantly into the realms of epigenetics and chromatin structuring.

This groundbreaking research broadens our understanding of ORC's functions, establishing it as a vital player in gene regulation and chromatin dynamics in human cells. These insights could have implications for understanding cancer biology and the mechanisms of gene expression regulation.

Study authors include Dutta, Zhangli Su, Ph.D., at UAB, and Chongzhi Zang, Ph.D., from the University of Virginia. The findings highlight a new chapter in ORC biology, emphasizing its dual roles in DNA replication and gene regulation.

Source: medicalxpress.com