Cellular memory modules

This experiment was able to identify a minimal cellular memory module of 219 bp originating from the Drosophila Fab-7 region which regulates the Abdominal-B gene. Recruitment of trxG proteins allows for binding to the DNA binding sites on the Zeste protein, overriding Zeste’s need for the Brahma (BRM) protein, and initiating the inheritance of active chromatin. Researchers then took this Zeste protein and mutated its binding sites which increased its role in PcG-dependent silencing. Preserved DNA sequence Ab-Fab recruits BRM and trxG proteins, activating embryogenesis and weakening the bind of PcG to Zeste protein. The effects of Ab-Fab allowed the Zeste protein to return to active chromatin states following its mutation. These response elements were determined to be cellular memory modules as there is DNA overlap and both elements express the memory of both silent and active chromatin by using cell division.[3] 

Polycomb repressive complexes (PRC) 1 and 2 are recruited to bind to the H3K27me3 gene, which is found at the beginning of Drosophila embryogenesis. PRC2 then catalyzes the gene’s methylation, inducing PCR2 recruitment and compacting the chromatin. The research found that PRC2 recruitment is dependent on the presence of the H2AKub sequence. However, even after mutations in the H3K27 residue, PcGs were able to be recruited and revert to their original phenotypes indicating a transcriptional change in the H3K27 residue.[7]

Cellular memory modules are extremely beneficial to synthetic biologists as they are a form of transcriptional memory. Transcription is a well-understood biological process and completes a large amount of the cell’s information processing. Due to this, synthetic biologists can develop synthetic memory devices used in experiments that increase our understanding of cellular processes. These devices can record stimulus exposure, maintain gene expression, and identify cell populations that respond to specific events along with tracking their progression throughout the response. This information can carry into disease research because if an event response correlates with future cell behavior, this can give scientists a greater understanding of diseases resulting from cellular inheritance like cancer.[8] Experimenters can use these synthetic memory devices to simulate specific events like exposure to potential disease risk factors to determine their physiological effects early on. This could have life-saving implications as we could receive information we normally only obtain after decades of exposure and disease formation significantly earlier on. This research could guide public health officials and policymakers on recommendations and regulations regarding these risk factors. Additionally, memory modules can accomplish long-term maintenance of their desired protein levels by using their output as regulatory input in order to perform new functions. This allows a memory module to assist in gene therapy, either curing or improving a person’s ability to fight disease.[8]

Misregulation of PcGs within cellular memory modules often leads to the development of cancerous tumors. PcG’s role is to regulate the transcription of developmental genes, which entail processes like cell cycle progression, differentiation, or stem cell plasticity. Due to its imperative role in biological processes, mutations among PcGs initiate tumorigenesis. PcG mutations are more prominent among hormone-dependent cancers where these proteins directly interact with the hormone receptors. It has been discovered that these PcG proteins are able to modulate the tumor microenvironment’s metabolism and immune response, impacting the cancer’s development. PcGs role in tumorigenesis isn’t fully understood although its link to cancer development is widely accepted.[9]