Cellular memory modules

Last updated

Cellular memory modules are a form of epigenetic inheritance that allow cells to maintain their original identity after a series of cell divisions and developmental processes. Cellular memory modules implement these preserved characteristics into transferred environments through transcriptional memory. [1] Cellular memory modules are primarily found in Drosophila .

Contents

History

Cellular memory modules were discovered by François Jacob and Jaques Monod in 1961 at the Pasteur Institute in Paris. The discovery led to Jacob and Monod, along with André Lwoff, receiving The Nobel Prize in Physiology or Medicine in 1965 for their discoveries regarding genetic control of enzyme and virus synthesis. These experimental results mapped the complex processes in which self-regulating processes express or suppress genes. Monod and Jacob proved how genetic information conversion during the construction of proteins was done through a messenger which evinced RNA. [2] Lwoff aided in the experiment that won the Nobel Prize but did not work on the series of experiments that led to the discovery of cellular memory modules, which is why he remains uncredited in its discovery.

Locations and mechanisms: experiment overviews

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. Cell memory modules.jpg
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, 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 (PcG) and trithorax group (trxG) proteins by using Polycomb- and trithorax response elements, which are just DNA sequences. [3] Transcription resets and alters epigenetic marks on chromosomal memory elements that are regulated by PcG and trxG proteins. [4] PcG genes maintain silent expression states during the development of 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 [5] by excluding transcriptional activators and making the gene unable to undergo RNA synthesis. [6] 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 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]  

H3K27 Mechanism

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]

Applications

Synthetic Memory Devices

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]

Cancer Development

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]

Related Research Articles

<span class="mw-page-title-main">Cellular differentiation</span> Developmental biology

Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. However, metabolic composition does get altered quite dramatically where stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. Thus, different cells can have very different physical characteristics despite having the same genome.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<span class="mw-page-title-main">Regulation of gene expression</span> Modifying mechanisms used by cells to increase or decrease the production of specific gene products

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

Polycomb-group proteins are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes through modulation of chromatin structure during embryonic development in fruit flies. They derive their name from the fact that the first sign of a decrease in PcG function is often a homeotic transformation of posterior legs towards anterior legs, which have a characteristic comb-like set of bristles.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

<span class="mw-page-title-main">Polycomb protein EED</span> Protein-coding gene in the species Homo sapiens

Polycomb protein EED is a protein that in humans is encoded by the EED gene.

<span class="mw-page-title-main">PHC2</span> Protein-coding gene in the species Homo sapiens

Polyhomeotic-like protein 2 is a protein that in humans is encoded by the PHC2 gene.

<span class="mw-page-title-main">ASH1L</span> Protein-coding gene in the species Homo sapiens

ASH1L is a histone-lysine N-methyltransferase enzyme encoded by the ASH1L gene located at chromosomal band 1q22. ASH1L is the human homolog of Drosophila Ash1.

Trithorax-group proteins (TrxG) are a heterogeneous collection of proteins whose main action is to maintain gene expression. They can be categorized into three general classes based on molecular function:

  1. histone-modifying TrxG proteins
  2. chromatin-remodeling TrxG proteins
  3. DNA-binding TrxG proteins,
<span class="mw-page-title-main">Tudor domain</span>

In molecular biology, a Tudor domain is a conserved protein structural domain originally identified in the Tudor protein encoded in Drosophila. The Tudor gene was found in a Drosophila screen for maternal factors that regulate embryonic development or fertility. Mutations here are lethal for offspring, inspiring the name Tudor, as a reference to the Tudor King Henry VIII and the several miscarriages experienced by his wives.

<span class="mw-page-title-main">PRC2</span>

PRC2 is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1.

M33 is a gene. It is a mammalian homologue of Drosophila Polycomb. It localises to euchromatin within interphase nuclei, but it is enriched within the centromeric heterochromatin of metaphase chromosomes. In mice, the official symbol of M33 gene styled Cbx2 and the official name chromobox 2 are maintained by the MGI. Also known as pc; MOD2. In human ortholog CBX2, synonyms CDCA6, M33, SRXY5 from orthology source HGNC. M33 was isolated by means of the structural similarity of its chromodomain. It contains a region of homology shared by Xenopus and Drosophila in the fifth exon. Polycomb genes in Drosophila mediate changes in higher-order chromatin structure to maintain the repressed state of developmentally regulated genes. It may also involved in the campomelic syndrome and neoplastic disorders linked to allele loss in this region. Disruption of the murine M33 gene, displayed posterior transformation of the sternal ribs and vertebral columns.

Plants depend on epigenetic processes for proper function. Epigenetics is defined as "the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence". The area of study examines protein interactions with DNA and its associated components, including histones and various other modifications such as methylation, which alter the rate or target of transcription. Epi-alleles and epi-mutants, much like their genetic counterparts, describe changes in phenotypes due to epigenetic mechanisms. Epigenetics in plants has attracted scientific enthusiasm because of its importance in agriculture.

Epigenetics of human development is the study of how epigenetics effects human development.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.

<span class="mw-page-title-main">Thomas Jenuwein</span> German scientist

Thomas Jenuwein is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.

Vincenzo Pirrotta is a biologist known for his work on Drosophila and polycomb group proteins. Born in Palermo, Italy, Pirotta migrated to the United States and enrolled at Harvard University. While at Harvard, he obtained undergraduate, graduate, and postdoctoral fellowships in physical chemistry and molecular biology. He later moved to Europe where he began studying gene regulation in bacteriophages and Drosophila. He was appointed assistant professor at the University of Basel in 1972. Pirotta returned to the United States, earning a full professorship at the Baylor College of Medicine in 1992. He then took up the position of professor of zoology at the University of Geneva in 2002, and in 2004 became a distinguished professor of molecular biology and biochemistry at Rutgers University.

H3R42me is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the mono-methylation at the 42nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

References

  1. Paro, Renato; Grossniklaus, Ueli; Santoro, Raffaella; Wutz, Anton (2021), Paro, Renato; Grossniklaus, Ueli; Santoro, Raffaella; Wutz, Anton (eds.), "Cellular Memory", Introduction to Epigenetics, Cham: Springer International Publishing, pp. 49–66, doi: 10.1007/978-3-030-68670-3_3 , ISBN   978-3-030-68670-3 , retrieved 2023-04-20
  2. "The Nobel Prize in Physiology or Medicine 1965". NobelPrize.org. Retrieved 2023-04-18.
  3. 1 2 Déjardin, Jérôme; Cavalli, Giacomo (2004-02-25). "Chromatin inheritance upon Zeste-mediated Brahma recruitment at a minimal cellular memory module". The EMBO Journal. 23 (4): 857–868. doi:10.1038/sj.emboj.7600108. ISSN   0261-4189. PMC   381013 . PMID   14963490.
  4. Rank, Gerhard; Prestel, Matthias; Paro, Renato (2002-11-01). "Transcription through Intergenic Chromosomal Memory Elements of the Drosophila Bithorax Complex Correlates with an Epigenetic Switch". Molecular and Cellular Biology. 22 (22): 8026–8034. doi:10.1128/MCB.22.22.8026-8034.2002. PMC   134728 . PMID   12391168.
  5. Bantignies, Frédéric; Cavalli, Giacomo (2006-06-01). "Cellular memory and dynamic regulation of polycomb group proteins". Current Opinion in Cell Biology. Nucleus and gene expression. 18 (3): 275–283. doi:10.1016/j.ceb.2006.04.003. ISSN   0955-0674.
  6. Orlando, Valerio (2003-03-07). "Polycomb, Epigenomes, and Control of Cell Identity". Cell. 112 (5): 599–606. doi: 10.1016/S0092-8674(03)00157-0 . ISSN   0092-8674. PMID   12628181.
  7. Marasca, Federica; Bodega, Beatrice; Orlando, Valerio (April 2018). "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". BioEssays. 40 (4): 1700137. doi:10.1002/bies.201700137. hdl: 10754/627331 .
  8. 1 2 Burrill, Devin R.; Silver, Pamela A. (2010-01-08). "Making Cellular Memories". Cell. 140 (1): 13–18. doi:10.1016/j.cell.2009.12.034. ISSN   0092-8674. PMC   2882105 . PMID   20085698.
  9. Parreno, Victoria; Martinez, Anne-Marie; Cavalli, Giacomo (March 2022). "Mechanisms of Polycomb group protein function in cancer". Cell Research. 32 (3): 231–253. doi: 10.1038/s41422-021-00606-6 . ISSN   1748-7838.