Advancements in technology have opened doors for scientists to delve deep into the complex world of genetic control elements, unveiling the intricate mechanisms governing gene activation within our genetic code. Contrary to the simplistic perception of cis-regulatory elements (CREs) as mere genetic on/off switches, emerging evidence underscores their capacity for nuanced behaviors. They’re not just toggles for gene enhancement; they orchestrate complex functions pivotal to sustaining cellular health.
New research originating from Japan has uncovered about 11,000 significant genetic switches, called housekeeping cis-regulatory elements (HK-CREs), which are active in every cell type. The study published in Nucleic Acids Research and led by Professor Kenta Nakai and Dr. Martin Loza from The Institute of Medical Science, The University of Tokyo, along with Dr. Alexis Vandenbon from Kyoto University, highlights the critical role of HK-CREs in maintaining cellular stability and function.
Dr. Loza emphasized the critical link between cancer and epigenetic mutations and shared the motivation behind their study. “Through extensive bioinformatics analyses, we aimed to emphasize HK-CREs’ profound impact on fundamental cellular processes, including their potential as essential housekeeping tumor suppressors.”
Their research illuminated a broader landscape: HK-CREs aren’t confined solely to regulating well-known housekeeping genes. Instead, they predominantly inhabit core promoter regions of numerous genes, surpassing the scope of typical housekeeping gene functions.
The research team conducted a thorough investigation using various public datasets related to epigenetics and gene expression to confirm the robustness and conservation of HK-CREs in 50 different healthy cell types. The analysis included data on histone modifications, DNA methylation, and RNA to provide a comprehensive evaluation.
Their meticulous approach aimed to pinpoint the genomic locations of these elements within unmethylated CpG-rich regions, a hallmark associated with their crucial housekeeping regulatory function.
“By leveraging bioinformatics analyses of multiomics data,” emphasized Dr. Loza, “we offer an approach to harnessing publicly available datasets for exploring diverse biological mechanisms.” This strategy, he noted, could significantly streamline analyses, reducing both time and financial investments required for comprehensive studies involving new data.
The team’s observations extended further, unveiling intricate interactions among housekeeping core promoters (HK-CPs), forming complex regulatory networks that transcend the influence of housekeeping genes to impact various cell-specific genes. In cancer cells, a subset of HK-CREs exhibited reduced activity across diverse cancer subtypes due to aberrant methylation, notably those linked to zinc finger genes in chromosome 19’s sub-telomere regions. This discovery shed light on potential housekeeping tumor suppressor genes like ZNF135, ZNF154, ZNF667, and ZNF667-AS1.
Dr. Loza highlighted the clinical relevance of their findings, citing decreased gene activity across multiple cancer cell lines and increased survival probability in cancers like pancreas adenocarcinoma and uveal melanoma. Ultimately, this research uncovered a novel class of HK-CREs pivotal for cellular stability, extending their influence well beyond regulating housekeeping genes.
Dr. Loza expressed optimism about leveraging these intrinsic genetic elements in developing cancer therapies, offering a unique avenue that could transcend the challenges of personalized medicine. “Our findings on housekeeping cis-regulatory elements fill a big gap in the current knowledge regarding gene regulatory processes,” he said. “We anticipate that our findings will enhance the understanding of these processes and serve as a valuable resource for researchers striving to uncover elements inherent in the genome for combating various diseases.”
Source: Martin Loza, Alexis Vandenbon, Kenta Nakai. Epigenetic characterization of housekeeping core promoters and their importance in tumor suppression. Nucleic Acids Research, September 21, 2023.
Reference: New Study Reveals Crucial ‘Housekeeping’ Genetic Elements and Their Potent Role to Fight Cancer. The Institute of Medical Science, The University of Tokyo. January 4, 2024.