Cellular memory modules: Difference between revisions

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'''Cellular memory modules''' are a form of [[Transgenerational epigenetic inheritance|epigenetic inheritance]] that allow cells to maintain their original identity after a series of [[Cell division|cell divisions]] and developmental processes. Cellular memory modules implement these preserved characteristics into transferred environments through [[transcriptional memory]].<ref>{{Citation |last=Paro |first=Renato |title=Cellular Memory |date=2021 |url=https://doi.org/10.1007/978-3-030-68670-3_3 |work=Introduction to Epigenetics |pages=49–66 |editor-last=Paro |editor-first=Renato |access-date=2023-04-20 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-030-68670-3_3 |isbn=978-3-030-68670-3 |last2=Grossniklaus |first2=Ueli |last3=Santoro |first3=Raffaella |last4=Wutz |first4=Anton |editor2-last=Grossniklaus |editor2-first=Ueli |editor3-last=Santoro |editor3-first=Raffaella |editor4-last=Wutz |editor4-first=Anton|doi-access=free |url-access=subscription }}</ref> Cellular memory modules are primarily found in ''[[Drosophila]]''.

== History ==

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== Locations and mechanisms: experiment overviews ==

[[File:Cell_memory_modules.jpg|thumb|PcG proteins repress transcription in salivary glands. A shows an active transcription. B shows transcription after addition of a promoter. C shows transcription of a mutant protein. D shows transcription become depressed.]]

Cellular memory modules have the same general process of genes undergoing [[Transcription (biology)|transcription]], these genes being transferred to an unfamiliar environment, and then these genes reverting to their original characteristics preserved through transcriptional memory. Cellular memory modules preserve repressed and active [[chromatin]] states in the [[Polycomb-group proteins|Polycomb group (PcG)]] and [[Trithorax-group proteins|trithorax group (trxG)]] proteins by using Polycomb- and trithorax [[response element]]s, which are just DNA sequences.<ref name=":0Déjardin-2004">{{Cite journal |last=Déjardin |first=Jérôme |last2=Cavalli |first2=Giacomo |date=2004-02-25 |title=Chromatin inheritance upon Zeste-mediated Brahma recruitment at a minimal cellular memory module |url=http://emboj.embopress.org/cgi/doi/10.1038/sj.emboj.7600108 |journal=The EMBO Journal |volume=23 |issue=4 |pages=857–868 |doi=10.1038/sj.emboj.7600108 |issn=0261-4189 |pmc=381013 |pmid=14963490}}</ref> Transcription resets and alters [[Epigenetic marker|epigenetic marks]] on chromosomal memory elements that are regulated by PcG and trxG proteins.<ref>{{Cite journal |last=Rank |first=Gerhard |last2=Prestel |first2=Matthias |last3=Paro |first3=Renato |date=2002-11-01 |title=Transcription through Intergenic Chromosomal Memory Elements of the Drosophila Bithorax Complex Correlates with an Epigenetic Switch |url=https://doi.org/10.1128/MCB.22.22.8026-8034.2002 |journal=Molecular and Cellular Biology |volume=22 |issue=22 |pages=8026–8034 |doi=10.1128/MCB.22.22.8026-8034.2002 |pmid=12391168|pmc=134728 }}</ref> PcG genes maintain silent expression states during the development of [[Hox gene|Hox genes]] while trxG proteins maintain Hox gene expression patterns. PcG proteins bind to Polycomb response elements (PREs) to repress the target gene and silence their transcription<ref>{{Cite journal |last=Bantignies |first=Frédéric |last2=Cavalli |first2=Giacomo |date=2006-06-01 |title=Cellular memory and dynamic regulation of polycomb group proteins |url=https://www.sciencedirect.com/science/article/pii/S0955067406000536 |journal=Current Opinion in Cell Biology |series=Nucleus and gene expression |language=en |volume=18 |issue=3 |pages=275–283 |doi=10.1016/j.ceb.2006.04.003 |issn=0955-0674|url-access=subscription }}</ref> by excluding [[transcriptional activators]] and making the gene unable to undergo RNA synthesis.<ref>{{Cite journal |last=Orlando |first=Valerio |date=2003-03-07 |title=Polycomb, Epigenomes, and Control of Cell Identity |url=https://www.cell.com/cell/abstract/S0092-8674(03)00157-0 |journal=Cell |language=English |volume=112 |issue=5 |pages=599–606 |doi=10.1016/S0092-8674(03)00157-0 |issn=0092-8674 |pmid=12628181|doi-access=free }}</ref> While the basis of the mechanism among cellular memory modules is the same, what initiates the mechanism and the specific proteins carrying it out differ based on the ___location of the cellular memory module within the gene. Some of these specific mechanisms and gene locations have been analyzed from experiments and outlined below.

=== Ab-Fab Mechanism ===

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 site|DNA binding sites]] on the Zeste protein, overriding Zeste’s need for the Brahma (BRM) protein, and initiating the inheritance of [[Active chromatin sequence|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 [[Embryo|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.<ref name=":0Déjardin-2004" /> 

=== H3K27 Mechanism ===

Polycomb repressive complexes (PRC) [[PRC1|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 [[DNA methylation|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 [[Phenotype|phenotypes]] indicating a transcriptional change in the H3K27 residue.<ref>{{Cite journal |last=Marasca |first=Federica |last2=Bodega |first2=Beatrice |last3=Orlando |first3=Valerio |date=April 2018 |title=How Polycomb-Mediated Cell Memory Deals With a Changing Environment: Variations in PcG complexes and proteins assortment convey plasticity to epigenetic regulation as a response to environment |url=https://onlinelibrary.wiley.com/doi/10.1002/bies.201700137 |journal=BioEssays |language=en |volume=40 |issue=4 |pages=1700137 |doi=10.1002/bies.201700137|hdl=10754/627331 |hdl-access=free }}</ref>

== Applications ==

=== Synthetic Memory Devices ===

Cellular memory modules are extremely beneficial to [[Synthetic biology|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]].<ref name=":1Burrill-2010">{{Cite journal |last=Burrill |first=Devin R. |last2=Silver |first2=Pamela A. |date=2010-01-08 |title=Making Cellular Memories |url=https://www.cell.com/cell/abstract/S0092-8674(09)01620-1 |journal=Cell |language=English |volume=140 |issue=1 |pages=13–18 |doi=10.1016/j.cell.2009.12.034 |issn=0092-8674 |pmc=2882105 |pmid=20085698}}</ref> . 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.<ref name=":1Burrill-2010" />

=== Cancer Development ===

Misregulation of PcGs within cellular memory modules often leads to the development of [[Neoplasm|cancerous tumors]]. PcG’s role is to regulate the transcription of developmental genes, which entail processes like [[cell cycle]] progression, [[Cellular differentiation|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|hormone-dependent cancers]] where these proteins directly interact with the [[Hormone receptor|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.<ref>{{Cite journal |last=Parreno |first=Victoria |last2=Martinez |first2=Anne-Marie |last3=Cavalli |first3=Giacomo |date=March 2022 |title=Mechanisms of Polycomb group protein function in cancer |url=https://www.nature.com/articles/s41422-021-00606-6 |journal=Cell Research |language=en |volume=32 |issue=3 |pages=231–253 |doi=10.1038/s41422-021-00606-6 |issn=1748-7838|doi-access=free |pmc=8888700 }}</ref>

== References ==

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