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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
Histone methylation is a marker of both active and inactive genes. Trimethylation of lysine 4 in H3K4 is linked to activated genes (79,80). Methylation at this site is associated with multiple other modifications such as acetylation by acetyltransferases (81) and deacetylation by deacetylases, the latter activity perhaps acting as a brake on genes actively transcribed by H3K4 methylation (82). On the other hand, some H3K4 interactions are specific for unmethylated DNA. The MLL enzymes, which can polymethylate H3K4 (83,84), exist as multicomponent complexes containing differing catalytic SET-related units (85). MLL1 in particular interacts with other modifiers such as the acetylases MOF and CBP (86), and along with other MLL enzymes also recruits the homeobox family genes. The Hox transcription factors play a role in embryonic development, as well as in angiogenesis, in which HoxD3, HoxB3, and HoxA9 are essential regulators. MLL1 is responsible for H3K4 trimethylation at the HoxA9 locus (86). It has recently been shown that suppression of MLL will inhibit Hox-related proangiogenic activity (87). A necessary component of the MLL complex that regulates Hox gene expression is menin, which specifically associates with MLL proteins among SET1 homologs. Menin is the protein encoded by Men1, which when mutated leads to multiple neoplasms, particularly in endocrine tissue (88). Hox gene expression is dependent upon the association of menin with MLL (89).
Noninvasive biomarkers to guide intervention: toward personalized patient management in prostate cancer
Published in Expert Review of Precision Medicine and Drug Development, 2020
Maria Frantzi, Enrique Gomez-Gomez, Harald Mischak
Zhao and colleagues [87] screened six previously reported [88] DNA methylation biomarkers including APC, GSTP1, homeobox D3 (HOXD3), kallikrein-10 (KLK10), T-Box Transcription Factor 15 (TBX15) and transforming growth factor beta-2 (TGFβ2) in urine samples from 408 patients directed to undergo prostate biopsy [87]. As in the previous studies, the cohort was subdivided into a training set of 268 PCa patients and a validation set of 140 PCa patients. A methylation biomarker panel based on the LASSO was developed including HOXD3 and GSTP1 genes, resulting in discriminating clinically significant from insignificant PCa with 59% sensitivity and 76% specificity [87].
Transient leukemia of Down syndrome
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Valentina Sas, Cristina Blag, Gabriela Zaharie, Emil Puscas, Cosmin Lisencu, Nicolae Andronic-Gorcea, Sergiu Pasca, Bobe Petrushev, Irina Chis, Mirela Marian, Delia Dima, Patric Teodorescu, Sabina Iluta, Mihnea Zdrenghea, Ioana Berindan-Neagoe, Gheorghe Popa, Sorin Man, Anca Colita, Cristina Stefan, Seiji Kojima, Ciprian Tomuleasa
When looking at microRNAs, miR-155, miR-802, miR-125b-2, let7c, and miR‑99a are overexpressed in DS and implicated in DS phenotypes [122,123]. MiR-125b-2 may have a role in the regulation of megakaryopoiesis and may be an oncogenic miRNA involved in the pathogenesis of megakaryoblastic leukemia of DS [124], as miR-486-5p cooperates with GATA1 and enhanced the survival of leukemic cells from patients with DS [125,126]. The variability of the phenotypes or the severity of DS may be due to changes in the epigenetic landscape [127]. Zhang et al. looked at chromosome 21 genes in DS and non-DS cells and found differences in promoter methylation of chromosome 21 genes [128]. The variability of DS phenotypes can be caused by the genetic or epigenetic background of each individual. The transcriptome analysis of monozygotic twins discordant for trisomy 21 highlights the existence of chromosomal domains of gene expression dysregulation between trisomic and normal fibroblasts. This observation includes not only the expression of protein-coding genes but also long non-coding RNAs (lncRNAs) [129,130]. Candidate genes on chromosome 21 that may contribute to epigenetic changes include holocarboxylase synthetase (HLCS), HMGN1, DYRK1α, RUNX1, and BRWD1 [131]. DNA methylation analysis of fibroblasts from a rare pair of monozygotic twins discordant for trisomy 21 combined with normal monozygotic twins and trisomy 21 monozygotic twins as controls, revealed differences in promoter regions of genes involved in embryonic organ morphogenesis such as HOXB5, HOXB6, HOXD3, HOXD10, and HOXD12 in trisomy 21. Although most of these loci are hyper-methylated in the twin with trisomy 21 compared to the normal twin, there is no enrichment for chromosome 21 genes. This highlights the point that the effect of the extra copy of chromosome 21 is not restricted to genes located on chromosome 21 and can modify the epigenetic status of loci located in the rest of the genome [132].