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The Parasite's Way of Life
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
For example, earlier in this chapter we discussed the transition of Plasmodium blood-stage merozoites into gametocytes, which are infective to blood-feeding mosquitoes. The conversion of merozoites to gametocytes requires the activity of a transcription factor called AP2-G. However, during repeated rounds of merozoite replication, the gene encoding this requisite transcription factor is associated with heterochromatin and is consequently not expressed. Maintenance of heterochromatin and continued silencing of the gene for AP2-G requires the association of a different protein called Heterochromatin Protein 1 (HP1), which forms part of the DNA-protein chromatin complex. As long as HP1 associates with chromatin, AP2-G cannot be produced, meaning that gametogenesis cannot take place.
Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Histone methyltransferase, G9a, is marked as an enzyme responsible for introducing the H3K9 dimethylation, a hallmark of euchromatin silencing [84,93,104,105]. HP1 (heterochromatin protein 1) binds with H3K9me2, which works in the recruitment of transcriptional repressors that prevent the active gene activation [106]. Although G9a-mediated methylation leads to the production of H3K9me2, the complex of G9a/GLP has also been demonstrated to methylate H1 [107,108] and also shows its contribution to the H3K27 methylation [93,109]. Further, G9a proved to have specific marked activity against numerous non-histone-based proteins by means of including itself, too [110]. However, the most well-studied G9a biology aspect is the repression of H3K9me2-based genetic expression. Moreover, from the various biochemical-based studies, it is clearly understood that G9a-based H3K9me2 is correlated with those regions of the genome that expressed at very low levels [87]. Still, the exact mechanisms that work in dynamic methylation pattern regulation mediated by Ehmt was unclear until now.
DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jesus Duque, Michael Lübbert, Mark Kirschbaum
H3K9 methylation, particularly trimethylation, is believed to be crucial to formation of heterochromatin (80), particularly as this methylation creates a binding site for the chromodomain (chromatin organization modifier) of the repression related protein HP1. Trimethylation at H3K9 is achieved by Suv39h1/Suv39h2 (94) which was the first HMT identified. This process is involved in several tumor-related signaling pathways, such as suppression achieved by Smads after TGF-b signaling (95), or suppression of cyclin E and E2F by Rb protein, the latter losing this suppressive ability when mutated (96,97). Relevant to our argument is that this repression requires the recruitment of HDACs (98). Furthermore, it appears that this Suv39h-HP1-mediated mechanism is intimately involved with DNMT3A and DNMT3B DNA methylating activity (99). It is worth noting that mice with decreased levels of Suv39h1 showed a high incidence of B-cell lymphomas (94). Of particular interest with regard to leukemia, it has been shown that residues 380–432 and 351–381 in the RUNX1 transcription factor, bind Suv39h1 as well as HDAC1 and 3 (100). RUNX1 is a component of fusion proteins found frequently in AML, such as t(8;21), t(12;21), and related to the activity inv(16); this relationship to H3K9 methylation may explain the release of lysosomal repression in cells with these mutations upon treatment with HDACi and hypomethylating agents (101). SETDB1, another enzyme which di- and trimethylates histones at H3K9, also interacts directly with DNMT3A and DNMT3B (102).
A systems biology approach to antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Wilian Augusto Cortopassi, Tanos Celmar Costa Franca, Antoniana Ursine Krettli
P. falciparum is able to bind to the intravascular host cell receptors through the major adhesion surface protein PfEMP1, which is encoded by 60 genes belonging to the var family. Only a single gene is expressed at a given time, and it alternates among other members of the family [74]. This is a well-understood mechanism by which the parasite avoids immune clearance. Different epigenetic modifications are shown to correlate with this gene activation/deactivation mechanism in P. falciparum. Di- and tri-methylation of lysine 4 of histone 3 (H3K4me2 and K3K4me3, respectively), as well as acetylation of lysine 9 of histone 3 (H3K9ac), are associated with activated genes, while silenced genes are enriched in tri-methylated lysine 9 of histone 3 (H3K9me3) [75,76]. Epigenetic eraser regulators such as PfSIR2A are responsible for the removal of the acetyl group of histone 3 (H3K9ac) and therefore are implicated in silencing of the var genes [77]. Other epigenetic proteins are also shown to have roles in gametocyte production. Heterochromatin protein 1 (PfHP1) is an epigenetic reader regulator that is able to bind to H3K9me3. Depletion of this gene results in gametocyte production, suggesting that proteins in the H3K9 tri-methylation pathway are potential targets for blocking parasite transmission to mosquitoes, although specificity for Plasmodium epigenetic regulators may also emerge as a challenge before these preclinical studies advance to clinical trials [78].
Protein biomarkers for subtyping breast cancer and implications for future research
Published in Expert Review of Proteomics, 2018
Claudius Mueller, Amanda Haymond, Justin B. Davis, Alexa Williams, Virginia Espina
Numerous potential biomarkers languish in the literature due to the need for rigorous validation studies prior to clinical adoption. Other emerging biomarkers relevant to breast cancer subtypes awaiting validation are mentioned here. A biomarker of interest is heterochromatin protein 1 family (HP1β), which regulates gene expression and DNA damage, as a potential prognostic and predictive biomarker for chemotherapy and PARP inhibitor treatment [117]. Evidence from gene expression, IHC, and MCF7 cell lines indicate that overexpression of HP1β was associated with poor prognosis [117]. A biomarker for radioiodine treatment of breast cancer may potentially be found in sodium–iodine symporter protein. Sodium–iodine symporter is overexpressed in ER+ breast cancer, with staining intensity equivalent to thyroid tissue [118]. Invasive tumors and DCIS express sodium iodide symporter more frequently than the normal adjacent tissue indicating that it could be a marker for radioiodine therapy [118]. Two studies indicate that the EpCAM expression was associated with worse overall survival [119,120]. Using IHC and clinicopathological data, EpCAM expression was shown to confer a poor prognosis in basal-like and luminal B HER2+ breast tumors [119,120]. Another extracellular matrix-associated protein, collagen 10a, has been shown by gene expression and IHC to be associated with poor prognosis in ER+/HER2+ breast tumors [121]. Sparse tumor infiltrating lymphocytes also correlated with lower frequency of pathological complete response. The combination of collagen 10a expression and the amount of tumor infiltrating lymphocytes had a higher predictive value [121].
Gordon H. Dixon’s trace in my personal career and the quantic jump experienced in regulatory information
Published in Systems Biology in Reproductive Medicine, 2018
It is also worth mentioning that in somatic cells of fly ovaries, transposon repression requires H1 and involves methylated H3K9. In this case, heterochromatization depends on the interaction of H1 with PIWI proteins and heterochromatin protein 1 (HP1) (Iwasaki et al. 2016). PIWI-interacting RNAs (piRNAs) guide PIWI dependent silencing machinery to deposit H3K9me3 at target genomic loci. Physical interaction between PIWI and H1 (in Drosophila melanogaster) facilitates H1 recruitment to transposon sequences, which contributes to chromatin compaction and heterochromatin formation (Lu et al. 2013; Iwasaki et al. 2016).