Статті в журналах: "Tissue specific methylation"

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Meng, Wei, Arnab Chakravarti, and Tim Lautenschlaeger. "Methylation-specific high-resolution melting analysis (MS-HRM)-based DNA promoter profiling in paired FFPE bladder cancer samples." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 315. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.315.

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315 Background: DNA methylation and histone modification are widely studied epigenetic events that can decrease gene expression levels. Promoter hypermethylation has been proposed as a potential diagnostic or prognostic biomarker in various cancers. We studied DNA promoter methylation of 5 cancer-associated genes (MRE11, APX1, ERCC1, RASSF1A and RASSF2A ) in paired FFPE bladder cancer tissues and normal adjacent tissue. The MRE11/Rad50/NBS1 complex serves as a single-strand DNA nuclease which participates in the repair of DNA double-strand breaks and replication errors. APX1 plays a key role in regulating H2O2 levels and H2O2 signaling. DNA repair machinery, ERCC1 protein levels in tumor tissue have been shown to predict response to platinum-based chemotherapy. RASSF1 is thought to be a tumor suppressor gene, while the function of RASSF2 is less well understood. Methods: 16 bladder cancer cases with available paraffin-embedded tumor and matched normal adjacent tissue specimens (32 tissue samples) were analyzed. DNA was extracted by Ambion RecoverAll Total Nucleic Acid Isolation kit. FFPE DNA bisulfite modification was performed using Zymo EZ DNA Methylation Kit. Methylation Specific-High Resolution Melting (MS-HRM) analysis was used to assess methylation status. MS-HRM monitors the melting behavior of PCR amplicons by using a DNA intercalating fluorescent dye. Results: MRE11 and APX1 promoters were not methylated in either cancer or normal adjacent samples. The ERCC1 gene was heavily methylated in 94% (30/32) of all cancer and wild type samples. RASSF1A and RASSF2A promoter methylation was significantly different between cancer and normal adjacent tissue. 50% (8/16) RASSF1A and 25% (4/16) RASSF2A had promoter methylation in cancer tissues, while only 6% (1/16) RASSF1A and 0% (0/16) RASSF2A had promoter methylation in normal adjacent tissues. 69% (11/16) of bladder cancer tissues were positive for RASSF1A or RASSF2A promotor methylation while only 1/16 normal adjacent tissue samples was positive for either promotor methylation. Conclusions: The results show that cancer and non-cancer tissue have different RASSF1A and RASSF2A promoter methylation patterns.

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Herzog, Emilie, Jubby Galvez, Anton Roks, Lisette Stolk, Michael Verbiest, Paul Eilers, Jan Cornelissen, Eric Steegers, and Régine Steegers-Theunissen. "Tissue-specific DNA methylation profiles in newborns." Clinical Epigenetics 5, no. 1 (2013): 8. http://dx.doi.org/10.1186/1868-7083-5-8.

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Williams, Ben P., Lindsey L. Bechen, Deborah A. Pohlmann, and Mary Gehring. "Somatic DNA demethylation generates tissue-specific methylation states and impacts flowering time." Plant Cell 34, no. 4 (December 25, 2021): 1189–206. http://dx.doi.org/10.1093/plcell/koab319.

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Abstract Cytosine methylation is a reversible epigenetic modification of DNA. In plants, removal of cytosine methylation is accomplished by the four members of the DEMETER (DME) family of 5-methylcytosine DNA glycosylases, named DME, DEMETER-LIKE2 (DML2), DML3, and REPRESSOR OF SILENCING1 (ROS1) in Arabidopsis thaliana. Demethylation by DME is critical for seed development, preventing experiments to determine the function of the entire gene family in somatic tissues by mutant analysis. Here, we bypassed the reproductive defects of dme mutants to create somatic quadruple homozygous mutants of the entire DME family. dme; ros1; dml2; and dml3 (drdd) leaves exhibit hypermethylated regions compared with wild-type leaves and rdd triple mutants, indicating functional redundancy among all four demethylases. Targets of demethylation include regions co-targeted by RNA-directed DNA methylation and, surprisingly, CG gene body methylation, indicating dynamic methylation at these less-understood sites. Additionally, many tissue-specific methylation differences are absent in drdd, suggesting a role for active demethylation in generating divergent epigenetic states across wild-type tissues. Furthermore, drdd plants display an early flowering phenotype, which involves 5′-hypermethylation and transcriptional down-regulation of FLOWERING LOCUS C. Active DNA demethylation is therefore required for proper methylation across somatic tissues and defines the epigenetic landscape of intergenic and coding regions.

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Khodosevich, K. V., Yu B. Lebedev, and E. D. Sverdlov. "The Tissue-Specific Methylation of Human-Specific Endogenous Retroviral LTRs." Russian Journal of Bioorganic Chemistry 30, no. 5 (September 2004): 441–45. http://dx.doi.org/10.1023/b:rubi.0000043787.07628.2a.

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Olumi, Aria F., Zongwei Wang, Rongbin Ge, Shulin Wu, Shahin Tabetabaei, and Chin-Lee Wu. "Epigenetic silencing and variable expression of SRD5A2 in specific compartments of human prostate." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 38. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.38.

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38 Background: The steroid-5α reductase type 2 gene (SRD5A2) and protein play a significant role in the development and growth of prostate tissue. SRD5A2 can be expressed in both the epithelial and stromal compartments of the prostate gland. Previously, we have shown that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene. Here we determined whether variability of SRD5A2 expression occurs in specific compartments of prostate tissues. Methods: Frozen and formalin-fixed sections of human adult prostate tissue was used. Laser capture microdissection (LCM) was performed to obtain a pure population of epithelial and stromal cells. Approximately 500–600 excised cells were captured, and the methylation pattern of SRD5A2 was determined by DNA methylation pull-down assay kit. The expression of SRD5A2 protein was identified with immunohistochemistry and quantitated by ELISA. Results: In the whole prostate tissue, samples with high SRD5A2 immunoreactivity had much lower levels of SRD5A2 promoter methylation compared to those with low SRD5A2 immunoreactivity. DNA methylation assay for the epithelial compartment closely resembled the findings of the whole prostate tissue. In contrast, the samples from the stromal compartment showed uniform methylation irrespective of the methylation pattern in the epithelial compartment or the whole tissue. The expression of SRD5A2 protein quantitated by ELISA further showed that the variable expression of SRD5A2 is better determined by epithelial compartment expression. Conclusions: Our data suggests that variability of SRD5A2 expression is dependent on the methylation pattern and expression of SRD5A2 in the epithelial compartment and not the stroma. Therefore, if epithelial expression of SRD5A2 is more representative of the whole prostatic tissue expression, then it is logical that SRD5A2 inhibitor’s efficacy is dependent on involution of the epithelial cells. Our findings will have broad implications for the use of 5ARIs in the treatment of BPH and for the chemoprevention of prostate cancer. Grant support: NIH/R01 DK091353

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Choi, Joe, and Nam. "Development of Tissue-Specific Age Predictors Using DNA Methylation Data." Genes 10, no. 11 (November 4, 2019): 888. http://dx.doi.org/10.3390/genes10110888.

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DNA methylation patterns have been shown to change throughout the normal aging process. Several studies have found epigenetic aging markers using age predictors, but these studies only focused on blood-specific or tissue-common methylation patterns. Here, we constructed nine tissue-specific age prediction models using methylation array data from normal samples. The constructed models predict the chronological age with good performance (mean absolute error of 5.11 years on average) and show better performance in the independent test than previous multi-tissue age predictors. We also compared tissue-common and tissue-specific aging markers and found that they had different characteristics. Firstly, the tissue-common group tended to contain more positive aging markers with methylation values that increased during the aging process, whereas the tissue-specific group tended to contain more negative aging markers. Secondly, many of the tissue-common markers were located in Cytosine-phosphate-Guanine (CpG) island regions, whereas the tissue-specific markers were located in CpG shore regions. Lastly, the tissue-common CpG markers tended to be located in more evolutionarily conserved regions. In conclusion, our prediction models identified CpG markers that capture both tissue-common and tissue-specific characteristics during the aging process.

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Pan, Zhangyuan, Xiangyu Wang, Ran Di, Qiuyue Liu, Wenping Hu, Xiaohan Cao, Xiaofei Guo, et al. "A 5-Methylcytosine Site of Growth Differentiation Factor 9 (GDF9) Gene Affects Its Tissue-Specific Expression in Sheep." Animals 8, no. 11 (November 7, 2018): 200. http://dx.doi.org/10.3390/ani8110200.

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Growth differentiation factor 9 (GDF9) plays an important role in the early folliculogenesis of sheep. This study investigated the mRNA expression of ovine GDF9 in different tissues by real-time PCR. GDF9 exhibits significantly higher levels of expression (p < 0.01) in the ovary, relative to other tissues, indicating that its expression is tissue specific. To explore the regulatory mechanism of this tissue-specific expression, the methylation level of one CpG island (−1453 to −1854) of GDF9 promoter in ovary and heart was determined. In this region (−1987 to −1750), only the mC-4 site was present in the Sp4 binding site showed differential methylation between the heart and ovary; with increased (p < 0.01) methylation being observed in the heart. Additionally, the methylation level was negatively correlated with GDF9 mRNA expression (R = −0.75, p = 0.012), indicating that the methylation of this site plays an important role in transcriptional regulation of GDF9. The methylation effect of the mC-4 site was confirmed by using dual-luciferase. Site-directed mutation (methylation) of mC-4 site significantly reduced (p < 0.05) basal transcriptional activity of GDF9 promoter in oocytes. These results imply that methylation of GDF9 promoter CpG island mC-4 site may affect the binding of the Sp4 transcription factor to the GDF9 promoter region in sheep, thereby regulating GDF9 expression and resulting in a tissue-specific expression.

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Yamasaki-Ishizaki, Yoko, Tomohiko Kayashima, Christophe K. Mapendano, Hidenobu Soejima, Tohru Ohta, Hideaki Masuzaki, Akira Kinoshita, et al. "Role of DNA Methylation and Histone H3 Lysine 27 Methylation in Tissue-Specific Imprinting of Mouse Grb10." Molecular and Cellular Biology 27, no. 2 (November 13, 2006): 732–42. http://dx.doi.org/10.1128/mcb.01329-06.

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ABSTRACT Mouse Grb10 is a tissue-specific imprinted gene with promoter-specific expression. In most tissues, Grb10 is expressed exclusively from the major-type promoter of the maternal allele, whereas in the brain, it is expressed predominantly from the brain type promoter of the paternal allele. Such reciprocally imprinted expression in the brain and other tissues is thought to be regulated by DNA methylation and the Polycomb group (PcG) protein Eed. To investigate how DNA methylation and chromatin remodeling by PcG proteins coordinate tissue-specific imprinting of Grb10, we analyzed epigenetic modifications associated with Grb10 expression in cultured brain cells. Reverse transcriptase PCR analysis revealed that the imprinted paternal expression of Grb10 in the brain implied neuron-specific and developmental stage-specific expression from the paternal brain type promoter, whereas in glial cells and fibroblasts, Grb10 was reciprocally expressed from the maternal major-type promoter. The cell-specific imprinted expression was not directly related to allele-specific DNA methylation in the promoters because the major-type promoter remained biallelically hypomethylated regardless of its activity, whereas gametic DNA methylation in the brain type promoter was maintained during differentiation. Histone modification analysis showed that allelic methylation of histone H3 lysine 4 and H3 lysine 9 were associated with gametic DNA methylation in the brain type promoter, whereas that of H3 lysine 27 regulated by the Eed PcG complex was detected in the paternal major-type promoter, corresponding to its allele-specific silencing. Here, we propose a molecular model that gametic DNA methylation and chromatin remodeling by PcG proteins during cell differentiation cause tissue-specific imprinting in embryonic tissues.

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Ząbek, Tomasz, Ewelina Semik, Agnieszka Fornal, Artur Gurgul, and Monika Bugno-Poniewierska. "The Relevance of Methylation Profiles of Equine ITGAL Gene." Annals of Animal Science 16, no. 3 (July 1, 2016): 711–20. http://dx.doi.org/10.1515/aoas-2015-0080.

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AbstractOne of epigenetic features of mammalian genomes is methylation of DNA. This nucleotide modification might exert suppressive effect on gene transcription. We have described putative relevance of methylation of one of immune cells related gene (ITGAL) observed in the set of 11 equine tissues. Comparison between qualitative RT-PCR results and DNA bisulfite sequencing of investigated set of tissues pointed to potential correlations between tissue specific methylation and tissue specific transcription in ITGAL locus. These findings might be important for studies on genetic and epigenetic background of autoimmune disorders in the horse.

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Beri, Silvana, Noemi Tonna, Giorgia Menozzi, Maria Clara Bonaglia, Carlo Sala, and Roberto Giorda. "DNA methylation regulates tissue-specific expression of Shank3." Journal of Neurochemistry 101, no. 5 (June 2007): 1380–91. http://dx.doi.org/10.1111/j.1471-4159.2007.04539.x.

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Thompson, Reid F., Gil Atzmon, Ciprian Gheorghe, Hong Qian Liang, Christina Lowes, John M. Greally, and Nir Barzilai. "Tissue-specific dysregulation of DNA methylation in aging." Aging Cell 9, no. 4 (May 22, 2010): 506–18. http://dx.doi.org/10.1111/j.1474-9726.2010.00577.x.

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Marzi, Sarah J., Emma L. Meaburn, Emma L. Dempster, Katie Lunnon, Jose L. Paya-Cano, Rebecca G. Smith, Manuela Volta, Claire Troakes, Leonard C. Schalkwyk, and Jonathan Mill. "Tissue-specific patterns of allelically-skewed DNA methylation." Epigenetics 11, no. 1 (January 2, 2016): 24–35. http://dx.doi.org/10.1080/15592294.2015.1127479.

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Muangsub, Tachapol, Jarunya Samsuwan, Pumipat Tongyoo, Nakarin Kitkumthorn, and Apiwat Mutirangura. "Analysis of methylation microarray for tissue specific detection." Gene 553, no. 1 (December 2014): 31–41. http://dx.doi.org/10.1016/j.gene.2014.09.060.

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Rohde, Kerstin, Maria Keller, Matthias Klös, Dorit Schleinitz, Arne Dietrich, Michael R. Schön, Daniel Gärtner, et al. "Adipose tissue depot specific promoter methylation of TMEM18." Journal of Molecular Medicine 92, no. 8 (April 26, 2014): 881–88. http://dx.doi.org/10.1007/s00109-014-1154-1.

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Agba, Ogechukwu Brenda, Ludwig Lausser, Klaus Huse, Christoph Bergmeier, Niels Jahn, Marco Groth, Martin Bens, et al. "Tissue-, sex-, and age-specific DNA methylation of rat glucocorticoid receptor gene promoter and insulin-like growth factor 2 imprinting control region." Physiological Genomics 49, no. 11 (November 1, 2017): 690–702. http://dx.doi.org/10.1152/physiolgenomics.00009.2017.

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Tissue-, sex-, and age-specific epigenetic modifications such as DNA methylation are largely unknown. Changes in DNA methylation of the glucocorticoid receptor gene ( NR3C1) and imprinting control region (ICR) of IGF2 and H19 genes during the lifespan are particularly interesting since these genes are susceptible to epigenetic modifications by prenatal stress or malnutrition. They are important regulators of development and aging. Methylation changes of NR3C1 affect glucocorticoid receptor expression, which is associated with stress sensitivity and stress-related diseases predominantly occurring during aging. Methylation changes of IGF2/H19 affect growth trajectory and nutrient use with risk of metabolic syndrome. Using a locus-specific approach, we characterized DNA methylation patterns of different Nr3c1 promoters and Igf2/H19 ICR in seven tissues of rats at 3, 9, and 24 mo of age. We found a complex pattern of locus-, tissue-, sex-, and age-specific DNA methylation. Tissue-specific methylation was most prominent at the shores of the Nr3c1 CpG island (CGI). Sex-specific differences in methylation peaked at 9 mo. During aging, Nr3c1 predominantly displayed hypomethylation mainly in females and at shores, whereas hypermethylation occurred within the CGI. Igf2/H19 ICR exhibited age-related hypomethylation occurring mainly in males. Methylation patterns of Nr3c1 in the skin correlated with those in the cortex, hippocampus, and hypothalamus. Skin may serve as proxy for methylation changes in central parts of the hypothalamic-pituitary-adrenal axis and hence for vulnerability to stress- and age-associated diseases. Thus, we provide in-depth insight into the complex DNA methylation changes of rat Nr3c1 and Igf2/H19 during aging that are tissue and sex specific.

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Baker, Emilie C., Audrey L. Earnhardt, Kubra Z. Cilkiz, Brittni P. Littlejohn, Haley C. Collins, Noushin Ghaffari, Penny K. Riggs, et al. "The Potential Use of DNA Methylation Patterns from Peripheral Blood Leukocytes as a Surrogate for Stress Axis Tissues in Mature Brahman Cows." Journal of Animal Science 99, Supplement_2 (May 1, 2021): 1–2. http://dx.doi.org/10.1093/jas/skab096.000.

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Abstract DNA methylation (DNAm) patterns are tissue specific and aid in tissue specific gene expression changes. The use of DNAm patterns from peripheral blood leukocytes (PBL) as a surrogate for patterns in other tissues is common, especially in longitudinal studies when sampling of tissues is not plausible. Thus, the objective of this study was to investigate the suitability of using DNAm patterns of PBL as a surrogate for the DNAm patterns in neuroendocrine tissues responsible for stress responses and energy metabolism. Samples from the paraventricular region of the hypothalamus, anterior pituitary gland, adrenal cortex, and the adrenal medulla were harvested from 5-yr-old Brahman cows (n = 8) and DNA was extracted from each sample. Methylation was assessed using reduced representation sodium bisulfite sequencing and differentially methylated regions (DMR) between the PBL DNA and tissue DNA were identified using EdgeR from Bioconductor, R. Analysis revealed over 15,000 DMRs located within promoter regions of genes in each tissue, with the majority of the sites having increased methylation in the PBL (Table 1). To further evaluate the use of PBL DNA as a surrogate, Pearson correlation values were calculated for genes (n = 20) pertinent to each respective tissue using the mean methylation of the specific gene in the PBL and in the tissue (Table 2). Three correlations were significant (P ≤ 0.05), two of which were negative. The sizable differences indicate that DNA methylation patterns from PBL do not compare well to patterns from hypothalamic, pituitary, adrenal cortex, and adrenal medulla tissues from 5-yr-old Brahman cows. This is especially the case for the majority of the specific genes examined in this study. Whether DNAm in the surrogate PBL will shift in a direction similar to that of specific tissues of Brahman cows exposed to stressful stimuli during developmental periods remains to be determined.

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Grant, DJ, H. Shi, and CT Teng. "Tissue and site-specific methylation correlates with expression of the mouse lactoferrin gene." Journal of Molecular Endocrinology 23, no. 1 (August 1, 1999): 45–55. http://dx.doi.org/10.1677/jme.0.0230045.

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We have previously examined the regulatory region of the mouse lactoferrin gene and have identified sequences essential for basal and hormonally induced expression. In this study, we explore the relationship between the methylation state of the mouse lactoferrin gene promoter and its expression in selected mouse tissues. In a transient expression system, transcriptional activity was blocked after in vitro methylation of the regulatory region of the mouse lactoferrin gene. In addition, the in vivo methylation state of three promoter region sites was assessed using Southern blot analysis of DNA digested with methylation-insensitive and -sensitive restriction enzymes. The results showed that site -455, upstream of the mouse lactoferrin estrogen response module, was highly unmethylated in DNA from both hormone-treated and -untreated mouse lung, liver, and spleen tissues. Also, in both treated and untreated samples, the -54 site is uniquely highly unmethylated in liver DNA, while the -22 site is unmethylated in spleen DNA. Northern blot analysis showed lactoferrin expression in tissues that were unmethylated at a minimum of two sites. These results show that the alteration of the methylation status of the three sites are tissue-specific and are associated with constitutive expression of lactoferrin.

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Yu, Da-Hai, Carol Ware, Robert A. Waterland, Jiexin Zhang, Miao-Hsueh Chen, Manasi Gadkari, Govindarajan Kunde-Ramamoorthy, Lagina M. Nosavanh, and Lanlan Shen. "Developmentally Programmed 3′ CpG Island Methylation Confers Tissue- and Cell-Type-Specific Transcriptional Activation." Molecular and Cellular Biology 33, no. 9 (March 4, 2013): 1845–58. http://dx.doi.org/10.1128/mcb.01124-12.

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During development, a small but significant number of CpG islands (CGIs) become methylated. The timing of developmentally programmed CGI methylation and associated mechanisms of transcriptional regulation during cellular differentiation, however, remain poorly characterized. Here, we used genome-wide DNA methylation microarrays to identify epigenetic changes during human embryonic stem cell (hESC) differentiation. We discovered a group of CGIs associated with developmental genes that gain methylation after hESCs differentiate. Conversely, erasure of methylation was observed at the identified CGIs during subsequent reprogramming to induced pluripotent stem cells (iPSCs), further supporting a functional role for the CGI methylation. Both global gene expression profiling and quantitative reverse transcription-PCR (RT-PCR) validation indicated opposing effects of CGI methylation in transcriptional regulation during differentiation, with promoter CGI methylation repressing and 3′ CGI methylation activating transcription. By studying diverse human tissues and mouse models, we further confirmed that developmentally programmed 3′ CGI methylation confers tissue- and cell-type-specific gene activationin vivo. Importantly, luciferase reporter assays provided evidence that 3′ CGI methylation regulates transcriptional activation via a CTCF-dependent enhancer-blocking mechanism. These findings expand the classic view of mammalian CGI methylation as a mechanism for transcriptional silencing and indicate a functional role for 3′ CGI methylation in developmental gene regulation.

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Zhu, Tianyu, Jacklyn Liu, Stephan Beck, Sun Pan, David Capper, Matt Lechner, Chrissie Thirlwell, Charles E. Breeze, and Andrew E. Teschendorff. "A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution." Nature Methods 19, no. 3 (March 2022): 296–306. http://dx.doi.org/10.1038/s41592-022-01412-7.

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AbstractBulk-tissue DNA methylomes represent an average over many different cell types, hampering our understanding of cell-type-specific contributions to disease development. As single-cell methylomics is not scalable to large cohorts of individuals, cost-effective computational solutions are needed, yet current methods are limited to tissues such as blood. Here we leverage the high-resolution nature of tissue-specific single-cell RNA-sequencing datasets to construct a DNA methylation atlas defined for 13 solid tissue types and 40 cell types. We comprehensively validate this atlas in independent bulk and single-nucleus DNA methylation datasets. We demonstrate that it correctly predicts the cell of origin of diverse cancer types and discovers new prognostic associations in olfactory neuroblastoma and stage 2 melanoma. In brain, the atlas predicts a neuronal origin for schizophrenia, with neuron-specific differential DNA methylation enriched for corresponding genome-wide association study risk loci. In summary, the DNA methylation atlas enables the decomposition of 13 different human tissue types at a high cellular resolution, paving the way for an improved interpretation of epigenetic data.

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Pangeson, Tanapat, Phanchana Sanguansermsri, Torpong Sanguansermsri, Teerapat Seeratanachot, Narutchala Suwanakhon, Metawee Srikummool, Worasak Kaewkong та Khwanruedee Mahingsa. "Association of Tissue-Specific DNA Methylation Alterations with α-Thalassemia Southeast Asian Deletion". Genetics & Epigenetics 9 (1 січня 2017): 1179237X1773610. http://dx.doi.org/10.1177/1179237x17736107.

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In the wild-type allele, DNA methylation levels of 10 consecutive CpG sites adjacent to the upstream 5′-breakpoint of α-thalassemia Southeast Asian (SEA) deletion are not different between placenta and leukocytes. However, no previous study has reported the map of DNA methylation in the SEA allele. This report aims to show that the SEA mutation is associated with DNA methylation changes, resulting in differential methylation between placenta and leukocytes. Methylation-sensitive high-resolution analysis was used to compare DNA methylation among placenta, leukocytes, and unmethylated control DNA. The result indicates that the DNA methylation between placenta and leukocyte DNA is different and shows that the CpG status of both is not fully unmethylated. Mapping of individual CpG sites was performed by targeted bisulfite sequencing. The DNA methylation level of the 10 consecutive CpG sites was different between placenta and leukocyte DNA. When the 10th CpG of the mutation allele was considered as a hallmark for comparing DNA methylation level, it was totally different from the unmethylated 10th CpG of the wild-type allele. Finally, the distinct DNA methylation patterns between both DNA were extracted. In total, 24 patterns were found in leukocyte samples and 9 patterns were found in placenta samples. This report shows that the large deletion is associated with DNA methylation change. In further studies for clinical application, the distinct DNA methylation pattern might be a potential marker for detecting cell-free fetal DNA.

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Peshavaria, M., and I. N. M. Day. "Methylation patterns in the human muscle-specific enolase gene (ENO3)." Biochemical Journal 292, no. 3 (June 15, 1993): 701–4. http://dx.doi.org/10.1042/bj2920701.

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The methylation status in the human-muscle enolase gene (ENO3) was assayed. Previous sequence data and MspI cleavage sites indicate the presence of a 5′ CpG-rich island of at least 4 kb: none of 22 characterized MspI CCGG sites is methylated in any of muscle, sperm or brain DNA. However a complex pattern of complete and partial methylation of MspI sites that is different between tissues is observed within the ENO3 gene: events at one site may be specific to muscle DNA. The absence of methylation in the promoter region of the ENO3 gene makes it unlikely that methylation plays a causal role either in transcriptional events or in the divergence of enolase-isogene regulation. The role of tissue-specific methylation events within ENO3 remains to be determined.

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Warnecke, Peter M., та Susan J. Clark. "DNA Methylation Profile of the Mouse Skeletal α-Actin Promoter during Development and Differentiation". Molecular and Cellular Biology 19, № 1 (1 січня 1999): 164–72. http://dx.doi.org/10.1128/mcb.19.1.164.

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ABSTRACT Genomic levels of DNA methylation undergo widespread alterations in early embryonic development. However, changes in embryonic methylation have proven difficult to study at the level of single-copy genes due to the small amount of tissue available for assay. This study provides the first detailed analysis of the methylation state of a tissue-specific gene through early development and differentiation. Using bisulfite sequencing, we mapped the methylation profile of the tissue-specific mouse skeletal α-actin promoter at all stages of development, from gametes to postimplantation embryos. We show that the α-actin promoter, which is fully methylated in the sperm and essentially unmethylated in the oocyte, undergoes a general demethylation from morula to blastocyst stages, although the blastula is not completely demethylated. Remethylation of the α-actin promoter occurs after implantation in a stochastic pattern, with some molecules being extensively methylated and others sparsely methylated. Moreover, we demonstrate that tissue-specific expression of the skeletal α-actin gene in the adult mouse does not correlate with the methylation state of the promoter, as we find a similar low level of methylation in both expressing and one of the two nonexpressing tissues tested. However, a subset of CpG sites within the skeletal α-actin promoter are preferentially methylated in liver, a nonexpressing tissue.

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Husby, Arild. "On the Use of Blood Samples for Measuring DNA Methylation in Ecological Epigenetic Studies." Integrative and Comparative Biology 60, no. 6 (August 24, 2020): 1558–66. http://dx.doi.org/10.1093/icb/icaa123.

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Synopsis There is increasing interest in understanding the potential for epigenetic factors to contribute to phenotypic diversity in evolutionary biology. One well studied epigenetic mechanism is DNA methylation, the addition of a methyl group to cytosines, which have the potential to alter gene expression depending on the genomic region in which it takes place. Obtaining information about DNA methylation at genome-wide scale has become straightforward with the use of bisulfite treatment in combination with reduced representation or whole-genome sequencing. While it is well recognized that methylation is tissue specific, a frequent limitation for many studies is that sampling-specific tissues may require sacrificing individuals, something which is generally undesirable and sometimes impossible. Instead, information about DNA methylation patterns in the blood is frequently used as a proxy tissue. This can obviously be problematic if methylation patterns in the blood do not reflect that in the relevant tissue. Understanding how, or if, DNA methylation in blood reflect DNA methylation patterns in other tissues is therefore of utmost importance if we are to make inferences about how observed differences in methylation or temporal changes in methylation can contribute to phenotypic variation. The aim of this review is to examine what we know about the potential for using blood samples in ecological epigenetic studies. I briefly outline some methods by which we can measure DNA methylation before I examine studies that have compared DNA methylation patterns across different tissues and, finally, examine how useful blood samples may be for ecological studies of DNA methylation. Ecological epigenetic studies are in their infancy, but it is paramount for the field to move forward to have detailed information about tissue and time dependence relationships in methylation to gain insights into if blood DNA methylation patterns can be a reliable bioindicator for changes in methylation that generate phenotypic variation in ecologically important traits.

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Sakowicz, Tomasz, Maria J. Olszewska, Piotr Łuchniak, and Joanna Kaźmierczak. "Tissue-specific DNA methylation in Haemanthus katharinae Bak. (Amaryllidaceae)." Acta Societatis Botanicorum Poloniae 67, no. 2 (2014): 175–80. http://dx.doi.org/10.5586/asbp.1998.020.

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The level of DNA methylation was compared in root meristem, adult leaf and endosperm of monocotyledonous species, <em>Haemanthus katharinae</em>, with the use of HPLC, restriction analysis, Southern blot hybridization and in situ nick-translation driven by restriction enzyme HhaI The highest level of 5-methylcytosine was observed in adult leaf whose nuclear chromatin is particularly condensed, and the lowest in endosperm. The level of DNA methylation of repetitive HaeIII 4006p sequence follows that of the total DNA.

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Karaglani, Makrina, Maria Panagopoulou, Ismini Baltsavia, Paraskevi Apalaki, Theodosis Theodosiou, Ioannis Iliopoulos, Ioannis Tsamardinos, and Ekaterini Chatzaki. "Tissue-Specific Methylation Biosignatures for Monitoring Diseases: An In Silico Approach." International Journal of Molecular Sciences 23, no. 6 (March 9, 2022): 2959. http://dx.doi.org/10.3390/ijms23062959.

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Tissue-specific gene methylation events are key to the pathogenesis of several diseases and can be utilized for diagnosis and monitoring. Here, we established an in silico pipeline to analyze high-throughput methylome datasets to identify specific methylation fingerprints in three pathological entities of major burden, i.e., breast cancer (BrCa), osteoarthritis (OA) and diabetes mellitus (DM). Differential methylation analysis was conducted to compare tissues/cells related to the pathology and different types of healthy tissues, revealing Differentially Methylated Genes (DMGs). Highly performing and low feature number biosignatures were built with automated machine learning, including: (1) a five-gene biosignature discriminating BrCa tissue from healthy tissues (AUC 0.987 and precision 0.987), (2) three equivalent OA cartilage-specific biosignatures containing four genes each (AUC 0.978 and precision 0.986) and (3) a four-gene pancreatic β-cell-specific biosignature (AUC 0.984 and precision 0.995). Next, the BrCa biosignature was validated using an independent ccfDNA dataset showing an AUC and precision of 1.000, verifying the biosignature’s applicability in liquid biopsy. Functional and protein interaction prediction analysis revealed that most DMGs identified are involved in pathways known to be related to the studied diseases or pointed to new ones. Overall, our data-driven approach contributes to the maximum exploitation of high-throughput methylome readings, helping to establish specific disease profiles to be applied in clinical practice and to understand human pathology.

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Schilling, Elmar, and Michael Rehli. "Global, comparative analysis of tissue-specific promoter CpG methylation." Genomics 90, no. 3 (September 2007): 314–23. http://dx.doi.org/10.1016/j.ygeno.2007.04.011.

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Igarashi, Jun, Satomi Muroi, Hiroyuki Kawashima, Xiaofei Wang, Yui Shinojima, Eiko Kitamura, Toshinori Oinuma, et al. "Quantitative analysis of human tissue-specific differences in methylation." Biochemical and Biophysical Research Communications 376, no. 4 (November 2008): 658–64. http://dx.doi.org/10.1016/j.bbrc.2008.09.044.

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Heinke, C., L. Andersen, S. Hagan, and K. S. Guise. "Tissue specific methylation of c-myc in adult chickens." Biochemical and Biophysical Research Communications 149, no. 1 (November 1987): 313–17. http://dx.doi.org/10.1016/0006-291x(87)91641-x.

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Nishioka, Yutaka. "Tissue specific methylation of human Y chromosomal DNA sequences." Tissue and Cell 20, no. 6 (January 1988): 875–80. http://dx.doi.org/10.1016/0040-8166(88)90028-6.

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30

Meer, Margarita, and Vadim Gladyshev. "DNA METHYLATION CLOCKS IN MOUSE." Innovation in Aging 3, Supplement_1 (November 2019): S970. http://dx.doi.org/10.1093/geroni/igz038.3516.

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Abstract One of important limiting factors in aging research is the time required to measure the effect of an intervention on lifespan. But this situation is now changing due to a recent discovery of DNA methylation-based markers (DNAm clocks). We developed a whole lifespan multi-tissue DNAm clock for mice with R2 =0.89. We also carried out comparative analyses of the available mouse DNAm clocks (single- or multi-tissue, based on different number of sites, based on one genomic locus or multi-loci). In general, tissue specific clocks are more accurate than muti-tissue clocks. We applied these tools to a variety of experimental systems, ranging from interventions to rejuvenation approaches, and analyzed various mouse tissues and public datasets. We further applied DNAm clocks to newly sequenced sets of blood and liver samples. Multi-loci blood clock outperforms other clocks when applied to blood samples, and the liver and multi-tissue clocks show similar precision on liver.

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Lehmann-Werman, Roni, Daniel Neiman, Hai Zemmour, Joshua Moss, Judith Magenheim, Adi Vaknin-Dembinsky, Sten Rubertsson, et al. "Identification of tissue-specific cell death using methylation patterns of circulating DNA." Proceedings of the National Academy of Sciences 113, no. 13 (March 14, 2016): E1826—E1834. http://dx.doi.org/10.1073/pnas.1519286113.

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Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.

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Basciano, Paul Andrew, Rita Shaknovich, Maria E. Figueroa та Paraskevi Giannakakou. "Differential DNA Methylation of TUBB1 Correlates with Tissue-Specific Hβ-1 Tubulin Expression". Blood 118, № 21 (18 листопада 2011): 4796. http://dx.doi.org/10.1182/blood.v118.21.4796.4796.

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Abstract Abstract 4796 Introduction: Hβ-1 tubulin is essential for normal thrombopoiesis and constitutes the majority of β-tubulin within the platelet marginal band. Hβ-1 tubulin has the highest sequence diversity from other tubulin isotypes, and has expression restricted to hematologic tissues. The best-characterized expression occurs in megakaryocytes, where temporal expression is limited to specific stages of megakaryocyte maturation. While expression of Hβ-1 tubulin has been shown to be dependent on transcription factors such as NF-E2, these factors have a multitude of gene targets and do not provide a full explanation of mechanisms responsible for specific Hβ-1 tubulin expression. Epigenetic regulation of gene transcription is now widely accepted as a mechanism of tissue-specific expression of gene products; however, the role of epigenetic regulation in the expression of tubulin isotypes has not been explored. Given the highly regulated expression of Hβ-1 tubulin and the potential of epigenetic modifications to drive specific gene expression, we hypothesized that epigenetic modulation via DNA methylation may be a mechanism for regulation of Hβ-1 tubulin expression. Methods: We identified 3 CpG-dense areas upstream and within TUBB1 (which encodes Hβ-1 tubulin) based on Human hg19 genome assembly. These areas included the putative promoter region (-2000 to +1bp from the 5'UTR) upstream of the transcriptional start site; a 3kb region spanning most of intron 1; and a region within exon 4. We used Sequenom MassARRAY EpiTYPER on bisulphite-converted DNA to quantitatively determine percent methylation at each CpG within the three CpG-dense regions. Specifically, we extracted genomic DNA from three cell lines expressing Hβ-1 tubulin (K562, MEG-01, and HEL), and six non-expressing cell lines (two hematologic cell lines (REH, KCL-22) and four epithelial cell lines (H1299, PC3, LNCap2, MDA-MB-231)), and performed bisulphite conversion of DNA. A difference of >25% was considered significant when comparing individual CpGs; methylation differences between CpGs across cell lines are reported as mean ± SEM. For each region, median methylation for each CpG was calculated across cell lines within a group, and regional methylation differences compared using the Mann-Whitney test. Results: Between 50–75% of CpGs within the three CpG-dense regions were available for analysis. In exon 4, there was no difference in overall methylation or methylation at any individual CpG between the Hβ-1 tubulin-expressing and non-expressing cell lines. In contrast, within intron 1, Hβ-1 tubulin-expressing cell lines were significantly hypomethylated compared to non-expressing cell lines (p=0.002). This difference was localized to a 1.5kb region within intron 1; mean methylation difference at each CpG within this region was 59±6%. The upstream promoter region similarly showed significant hypomethylation in Hβ-1 tubulin-expressing cell lines (p=0.001); the differentially methylated CpGs were localized to a 350bp region just upstream of the transcription start site, and mean methylation difference was 60±16% at each CpG. Methylation patters were highly similar between CpGs within each group (i.e. Hβ-1 tubulin-expressing or non-expressing cell lines), with only 10% of individual CpGs showing >15% methylation difference between cell lines of the same group. Conclusion: We found significant extra- and intra-genic DNA methylation differences in TUBB1 between Hβ-1 tubulin-expressing and non-expressing cell lines. Methylation changes were localized to two CpG-dense regions, namely the upstream promoter region and intron 1 of TUBB1, while a third region in exon 4 showed no differences in methylation. The overall methylation differences within the regions were attributable to large methylation differences at individual CpGs localized to particular areas within those regions. Taken together, these results suggest that tissue-specific expression of Hβ-1 tubulin may be regulated in part by highly-specific changes in DNA methylation of TUBB1. To our knowledge, this is the first report of epigenetic modulation associated with tissue-specific tubulin isotype expression. Further work is underway to confirm these findings in normal primary hematopoietic tissues and to investigate their associations with temporal expression of Hβ-1 tubulin during megakaryocyte development. Disclosures: No relevant conflicts of interest to declare.

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Mullins, L. J., G. Veres, C. T. Caskey, and V. Chapman. "Differential methylation of the ornithine carbamoyl transferase gene on active and inactive mouse X chromosomes." Molecular and Cellular Biology 7, no. 11 (November 1987): 3916–22. http://dx.doi.org/10.1128/mcb.7.11.3916-3922.1987.

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Ornithine carbamoyl transferase (Oct) is an X-linked gene which exhibits tissue-specific expression. To determine whether methylation of specific CpG sequences plays a role in dosage compensation or tissue-specific expression of the gene, 13 potentially methylatable sites were identified over a 30-kilobase (kb) region spanning from approximately 15 kb upstream to beyond exon II. Fragments of the Mus hortulanus Oct gene were used as probes to establish the degree of methylation at each site. By considering the methylation status in liver (expressing tissue) versus kidney (nonexpressing tissue) from male and female mice, the active and inactive genes could be investigated on active and inactive X-chromosome backgrounds. One MspI site, 12 kb 5' of the Oct-coding region, was cleaved by HpaII in liver DNA from males but not in kidney DNA from males and thus exhibited complete correlation with tissue-specific expression of the gene. Six other sites showed partial methylation, reflecting incomplete correlation with tissue-specific expression.

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Mullins, L. J., G. Veres, C. T. Caskey, and V. Chapman. "Differential methylation of the ornithine carbamoyl transferase gene on active and inactive mouse X chromosomes." Molecular and Cellular Biology 7, no. 11 (November 1987): 3916–22. http://dx.doi.org/10.1128/mcb.7.11.3916.

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Ornithine carbamoyl transferase (Oct) is an X-linked gene which exhibits tissue-specific expression. To determine whether methylation of specific CpG sequences plays a role in dosage compensation or tissue-specific expression of the gene, 13 potentially methylatable sites were identified over a 30-kilobase (kb) region spanning from approximately 15 kb upstream to beyond exon II. Fragments of the Mus hortulanus Oct gene were used as probes to establish the degree of methylation at each site. By considering the methylation status in liver (expressing tissue) versus kidney (nonexpressing tissue) from male and female mice, the active and inactive genes could be investigated on active and inactive X-chromosome backgrounds. One MspI site, 12 kb 5' of the Oct-coding region, was cleaved by HpaII in liver DNA from males but not in kidney DNA from males and thus exhibited complete correlation with tissue-specific expression of the gene. Six other sites showed partial methylation, reflecting incomplete correlation with tissue-specific expression.

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Lee, Kibaick, Sanghoon Moon, Mi-Jin Park, In-Uk Koh, Nak-Hyeon Choi, Ho-Yeong Yu, Young Jin Kim, et al. "Integrated Analysis of Tissue-Specific Promoter Methylation and Gene Expression Profile in Complex Diseases." International Journal of Molecular Sciences 21, no. 14 (July 17, 2020): 5056. http://dx.doi.org/10.3390/ijms21145056.

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This study investigated whether the promoter region of DNA methylation positively or negatively regulates tissue-specific genes (TSGs) and if it correlates with disease pathophysiology. We assessed tissue specificity metrics in five human tissues, using sequencing-based approaches, including 52 whole genome bisulfite sequencing (WGBS), 52 RNA-seq, and 144 chromatin immunoprecipitation sequencing (ChIP-seq) data. A correlation analysis was performed between the gene expression and DNA methylation levels of the TSG promoter region. The TSG enrichment analyses were conducted in the gene–disease association network (DisGeNET). The epigenomic association analyses of CpGs in enriched TSG promoters were performed using 1986 Infinium MethylationEPIC array data. A correlation analysis showed significant associations between the promoter methylation and 449 TSGs’ expression. A disease enrichment analysis showed that diabetes- and obesity-related diseases were high-ranked. In an epigenomic association analysis based on obesity, 62 CpGs showed statistical significance. Among them, three obesity-related CpGs were newly identified and replicated with statistical significance in independent data. In particular, a CpG (cg17075888 of PDK4), considered as potential therapeutic targets, were associated with complex diseases, including obesity and type 2 diabetes. The methylation changes in a substantial number of the TSG promoters showed a significant association with metabolic diseases. Collectively, our findings provided strong evidence of the relationship between tissue-specific patterns of epigenetic changes and metabolic diseases.

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Lu, Qianjin, Donna Ray, David Gutsch, and Bruce Richardson. "Effect of DNA methylation and chromatin structure onITGAL expression." Blood 99, no. 12 (June 15, 2002): 4503–8. http://dx.doi.org/10.1182/blood.v99.12.4503.

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LFA-1 (CD11a/CD18, αLβ2) is an integrin expressed in a tissue-specific fashion and is important in inflammatory and immune responses. Promoter analysis has identified transcription factors that may be involved in CD11a expression, but the mechanisms contributing to its tissue-specific expression are incompletely characterized. In this report we have asked if DNA methylation and/or chromatin structure could contribute to tissue-specific CD11a expression. Bisulfite sequencing was used to compare methylation patterns in the promoter and 5′ flanking regions of the ITGAL gene, encoding CD11a, in normal human T cells, which express LFA-1, and fibroblasts, which do not. The region was found to be heavily methylated in fibroblasts but not T cells, and methylation correlated with an inactive chromatin configuration as analyzed by deoxyribonuclease 1 sensitivity. Patch methylation of the promoter region revealed that promoter activity was methylation-sensitive but that methylation of the 5′ flanking regions more than 500 base pairs 5′ to the transcription start site could also suppress promoter function. Treating fibroblasts with a DNA methylation inhibitor decreased ITGAL promoter methylation and increased CD11a messenger RNA. The results thus indicate that methylation and chromatin structure may contribute to the tissue-specific expression of CD11a.

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Racanelli, Alexandra C., Fiona B. Turner, Lin-Ying Xie, Shirley M. Taylor, and Richard G. Moran. "A Mouse Gene That Coordinates Epigenetic Controls and Transcriptional Interference To Achieve Tissue-Specific Expression." Molecular and Cellular Biology 28, no. 2 (November 12, 2007): 836–48. http://dx.doi.org/10.1128/mcb.01088-07.

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ABSTRACT The mouse fpgs gene uses two distantly placed promoters to produce functionally distinct isozymes in a tissue-specific pattern. We queried how the P1 and P2 promoters were differentially controlled. DNA methylation of the CpG-sparse P1 promoter occurred only in tissues not initiating transcription at this site. The P2 promoter, which was embedded in a CpG island, appeared open to transcription in all tissues by several criteria, including lack of DNA methylation, yet was used only in dividing tissues. The patterns of histone modifications over the two promoters were very different: over P1, histone activation marks (acetylated histones H3 and H4 and H3 trimethylated at K4) reflected transcriptional activity and apparently reinforced the effects of hypomethylated CpGs; over P2, these marks were present in tissues whether P2 was active, inactive, or engaged in assembly of futile initiation complexes. Since P1 transcriptional activity coexisted with silencing of P2, we sought the mechanism of this transcriptional interference. We found RNA polymerase II, phosphorylated in a pattern consistent with transcriptional elongation, and only minimal levels of initiation factors over P2 in liver. We concluded that mouse fpgs uses DNA methylation to control tissue-specific expression from a CpG-sparse promoter, which is dominant over a downstream promoter masked by promoter occlusion.

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Hoivik, Erling A., Trine E. Bjanesoy, Oliver Mai, Shiki Okamoto, Yasuhiko Minokoshi, Yuichi Shima, Ken-ichirou Morohashi, Ulrich Boehm, and Marit Bakke. "DNA Methylation of Intronic Enhancers Directs Tissue-Specific Expression of Steroidogenic Factor 1/Adrenal 4 Binding Protein (SF-1/Ad4BP)." Endocrinology 152, no. 5 (February 22, 2011): 2100–2112. http://dx.doi.org/10.1210/en.2010-1305.

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The nuclear receptor steroidogenic factor 1/adrenal 4 binding protein (SF-1/Ad4BP) is an essential regulator of endocrine development and function, and the expression of the corresponding gene (sf-1/ad4bp) is precisely regulated in a time- and tissue-dependent manner. We previously demonstrated that the basal promoter of sf-1/ad4bp is controlled by DNA methylation and that its methylation status reflects the expression pattern of SF-1/Ad4BP. Recently, three intronic enhancers were identified in the sf-1/ad4bp gene that target SF-1/Ad4BP expression to the fetal adrenal (FAdE; fetal adrenal-specific enhancer), to pituitary gonadotropes (PGE; pituitary gonadotrope-specific enhancer), and to the ventromedial hypothalamic nucleus (VMHE; ventromedial hypothalamic nucleus-specific enhancer). Here, we demonstrate that the activity of these enhancers is correlated with their DNA methylation status. We show that they are hypomethylated in tissues where they are active and generally hypermethylated in tissues where they are not active. Furthermore, we demonstrate in transient transfection experiments that forced DNA methylation represses reporter gene activity driven by these enhancers. These data directly demonstrate a functional significance for the enhancers' methylation status. Intriguingly, further analyses of the basal promoter in gonadotropes revealed that it is methylated in these cells, in contrast to other SF-1/Ad4BP-expressing tissues. Consistent with this, sf-1/ad4bp is transcribed from an alternative promoter in gonadotropes. Taken together, our experiments show that the tissue-specific expression of SF-1/Ad4BP is epigenetically regulated and identify tissue-specific differentially methylated regions within the sf-1/ad4bp locus that are essential for its transcriptional control.

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Eskandari-Nasab, Ebrahim, Mohammad Hashemi, and Firoozeh Rafighdoost. "Promoter Methylation and mRNA Expression of Response Gene to Complement 32 in Breast Carcinoma." Journal of Cancer Epidemiology 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/7680523.

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Background. Response gene to complement 32 (RGC32), induced by activation of complements, has been characterized as a cell cycle regulator; however, its role in carcinogenesis is still controversial. In the present study we comparedRGC32promoter methylation patterns and mRNA expression in breast cancerous tissues and adjacent normal tissues.Materials and Methods. Sixty-three breast cancer tissues and 63 adjacent nonneoplastic tissues were included in our study.Design. Nested methylation-specific polymerase chain reaction (Nested-MSP) and quantitative PCR (qPCR) were used to determineRGC32promoter methylation status and its mRNA expression levels, respectively.Results. RGC32 methylation pattern was not different between breast cancerous tissue and adjacent nonneoplastic tissue (OR = 2.30, 95% CI = 0.95–5.54). However, qPCR analysis displayed higher levels ofRGC32mRNA in breast cancerous tissues than in noncancerous tissues (1.073 versus 0.959;P=0.001), irrespective of the promoter methylation status. The expression levels and promoter methylation ofRGC32were not correlated with any of patients’ clinical characteristics (P>0.05).Conclusion. Our findings confirmed upregulation of RGC32 in breast cancerous tumors, but it was not associated with promoter methylation patterns.

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Singh, Devika, Dan Sun, Andrew G. King, David E. Alquezar-Planas, Rebecca N. Johnson, David Alvarez-Ponce, and Soojin V. Yi. "Koala methylomes reveal divergent and conserved DNA methylation signatures of X chromosome regulation." Proceedings of the Royal Society B: Biological Sciences 288, no. 1945 (February 24, 2021): 20202244. http://dx.doi.org/10.1098/rspb.2020.2244.

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X chromosome inactivation (XCI) mediated by differential DNA methylation between sexes is an iconic example of epigenetic regulation. Although XCI is shared between eutherians and marsupials, the role of DNA methylation in marsupial XCI remains contested. Here, we examine genome-wide signatures of DNA methylation across fives tissues from a male and female koala ( Phascolarctos cinereus ), and present the first whole-genome, multi-tissue marsupial ‘methylome atlas’. Using these novel data, we elucidate divergent versus common features of representative marsupial and eutherian DNA methylation. First, tissue-specific differential DNA methylation in koalas primarily occurs in gene bodies. Second, females show significant global reduction (hypomethylation) of X chromosome DNA methylation compared to males. We show that this pattern is also observed in eutherians. Third, on average, promoter DNA methylation shows little difference between male and female koala X chromosomes, a pattern distinct from that of eutherians. Fourth, the sex-specific DNA methylation landscape upstream of Rsx , the primary lnc RNA associated with marsupial XCI, is consistent with the epigenetic regulation of female-specific (and presumably inactive X chromosome-specific) expression. Finally, we use the prominent female X chromosome hypomethylation and classify 98 previously unplaced scaffolds as X-linked, contributing an additional 14.6 Mb (21.5%) to genomic data annotated as the koala X chromosome. Our work demonstrates evolutionarily divergent pathways leading to functionally conserved patterns of XCI in two deep branches of mammals.

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Kidambi, Srividya, Xiaoqing Pan, Chun Yang, Pengyuan Liu, Michelle L. Roberts, Yingchuan Li, Tao Wang, et al. "Dietary Sodium Restriction Results in Tissue-Specific Changes in DNA Methylation in Humans." Hypertension 78, no. 2 (August 2021): 434–46. http://dx.doi.org/10.1161/hypertensionaha.120.17351.

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Dietary sodium affects blood pressure (BP) and vascular function. Animal studies suggest epigenetic changes (eg, DNA methylation) are involved. We hypothesized that sodium restriction induces methylation changes in T cells and arterioles in humans. Fifty subjects (49% women) were placed on 1200-mg sodium/day diet for 2 weeks. BP and brachial artery flow-mediated dilation were evaluated. Methylation sequencing (pre- and post-diet) was performed on T-cell (n=50) and biopsied arteriolar (n=10) DNA. RNA sequencing was also performed on arterioles (n=11). Over 2 weeks, mean sodium consumption was 946 mg/day. Average BP reductions after low-sodium intake were −8±13/−4±9 mm Hg ( P <0.001). Flow-mediated dilation improved (5.8±2.9% to 6.8±3.4%; P =0.03). T-cell DNA was substantially more methylated than arterioles. The differentially methylated regions (false discovery rate, <0.05) identified in T cells and arterioles after sodium restriction were located in 117 and 71 genes, respectively. Four genes were identified in both T cells and arterioles ( P =0.009 for the overlap). The dietary effects on methylation in several DNA regions were associated with dietary effects on BP. Several differentially expressed genes in arterioles contained differentially methylated regions at the significance level of P <0.05. In addition, 46 genes contained differentially methylated regions in both human and SS/Mcw rat T cells ( P =0.03 for the overlap). Sodium restriction significantly affected DNA methylation in T cells and arterioles, some of which are associated with BP. Methylation patterns and sodium effects on methylation are largely tissue specific but also have overlaps between tissues and species. These findings may lead to better understanding of dietary sodium interactions with cellular processes and, therefore, novel therapeutic targets.

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Yang, Lixin, Hong Yang, Jingnan Li, Jianyu Hao, and Jiaming Qian. "ppENKGene Methylation Status in the Development of Pancreatic Carcinoma." Gastroenterology Research and Practice 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/130927.

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Objective. To explore the association of hypermethylation of the proenkephalin gene (ppENK) with pancreatic carcinoma and to identify the effects of a demethylating agent on pancreatic cell lines.Method. Human pancreatic cancer tissues and five pancreatic carcinoma cell lines, as well as normal pancreatic tissue, were used.ppENKmethylation status was detected by MS-PCR (methylation-specific PCR).Results. Methylation ofppENKwas detected in 90.3% (28/31) of the human pancreatic carcinoma tissues but was not seen in normal pancreatic tissue. There was no correlation between the extent of methylation ofppENKand the clinicopathological features of the pancreatic carcinomas. MethylatedppENKwas detected in all the pancreatic cancer cell lines and was associated with loss of mRNA expression in the pancreatic carcinoma cell lines and normal pancreatic tissue. After treatment with 5-aza-dC, methylatedppENKwas not detected and the inhibition ofppENKmRNA expression was reversed.Conclusions. Inhibition ofppENKexpression by a change in its methylation status plays an important role in pancreatic carcinogenesis.ppENKmethylation is thus an important molecular event that distinguishes pancreatic carcinoma tissue from normal pancreatic tissue. Effects on cell growth, apoptosis, and the cell cycle may contribute to changes ofppENKmethylation status.

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Müller, Carsten, Carol Readhead, Sven Diederichs, Gregory Idos, Rong Yang, Nicola Tidow, Hubert Serve, Wolfgang E. Berdel, and H. Phillip Koeffler. "Methylation of the Cyclin A1 Promoter Correlates with Gene Silencing in Somatic Cell Lines, while Tissue-Specific Expression of Cyclin A1 Is Methylation Independent." Molecular and Cellular Biology 20, no. 9 (May 1, 2000): 3316–29. http://dx.doi.org/10.1128/mcb.20.9.3316-3329.2000.

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ABSTRACT Gene expression in mammalian organisms is regulated at multiple levels, including DNA accessibility for transcription factors and chromatin structure. Methylation of CpG dinucleotides is thought to be involved in imprinting and in the pathogenesis of cancer. However, the relevance of methylation for directing tissue-specific gene expression is highly controversial. The cyclin A1 gene is expressed in very few tissues, with high levels restricted to spermatogenesis and leukemic blasts. Here, we show that methylation of the CpG island of the human cyclin A1 promoter was correlated with nonexpression in cell lines, and the methyl-CpG binding protein MeCP2 suppressed transcription from the methylated cyclin A1 promoter. Repression could be relieved by trichostatin A. Silencing of a cyclin A1 promoter-enhanced green fluorescent protein (EGFP) transgene in stable transfected MG63 osteosarcoma cells was also closely associated with de novo promoter methylation. Cyclin A1 could be strongly induced in nonexpressing cell lines by trichostatin A but not by 5-aza-cytidine. The cyclin A1 promoter-EGFP construct directed tissue-specific expression in male germ cells of transgenic mice. Expression in the testes of these mice was independent of promoter methylation, and even strong promoter methylation did not suppress promoter activity. MeCP2 expression was notably absent in EGFP-expressing cells. Transcription from the transgenic cyclin A1 promoter was repressed in most organs outside the testis, even when the promoter was not methylated. These data show the association of methylation with silencing of the cyclin A1 gene in cancer cell lines. However, appropriate tissue-specific repression of the cyclin A1 promoter occurs independently of CpG methylation.

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Alvizo-Rodriguez, Carlos Rogelio, Maria de la Luz Ayala-Madrigal, Jesus Arturo Hernandez-Sandoval, Helen Haydee Fernanda Ramirez-Plascencia, Christian Octavio Gonzalez-Villaseñor, Nelly Margarita Macias-Gomez, Jorge Peregrina-Sandoval, et al. "Methylation analysis of MIR200 family in Mexican patients with colorectal cancer." Journal of Investigative Medicine 68, no. 3 (December 23, 2019): 782–85. http://dx.doi.org/10.1136/jim-2019-001184.

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The present study aimed to analyze the methylation pattern of the MIR200 family in the colorectal tissues and peripheral blood of colorectal cancer (CRC) patients. Previous informed consent, 102 samples of colorectal tissues (tumor and adjacent normal tissues) and 40 peripheral blood samples were collected from CRC patients. Additionally, we included a reference group of 40 blood samples. DNA extraction was done for colorectal tissues and peripheral blood. For methylation-specific PCR, we used bisulfite-treated DNA and controls for methylated and unmethylated DNA were included to each assay. PCR fragments were separated by 6% polyacrylamide gel electrophoresis. Methylation-positive and methylation-negative results were confirmed by bisulfite genomic sequencing technique. We analyzed 102 colorectal tissues and 40 blood samples from 51 CRC patients. MIR200B/MIR200A/MIR429 methylation analysis discloses no differences among tissues (p>0.05). However, MIR200C/MIR141 methylation showed differences between colorectal tissues and peripheral blood of CRC patients (p<0.0001) and mainly methylated alleles were observed in peripheral blood. These findings suggest a tissue-specific methylation pattern for the MIR200C/MIR141 promoter.

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Hoivik, Erling A., Linda Aumo, Reidun Aesoy, Haldis Lillefosse, Aurélia E. Lewis, Rebecca M. Perrett, Nancy R. Stallings, Neil A. Hanley, and Marit Bakke. "Deoxyribonucleic Acid Methylation Controls Cell Type-Specific Expression of Steroidogenic Factor 1." Endocrinology 149, no. 11 (July 24, 2008): 5599–609. http://dx.doi.org/10.1210/en.2008-0104.

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Steroidogenic factor 1 (SF1) is expressed in a time- and cell-specific manner in the endocrine system. In this study we present evidence to support that methylation of CpG sites located in the proximal promoter of the gene encoding SF1 contributes to the restricted expression pattern of this nuclear receptor. DNA methylation analyses revealed a nearly perfect correlation between the methylation status of the proximal promoter and protein expression, such that it was hypomethylated in cells that express SF1 but hypermethylated in nonexpressing cells. Moreover, in vitro methylation of this region completely repressed reporter gene activity in transfected steroidogenic cells. Bisulfite sequencing of DNA from embryonic tissue demonstrated that the proximal promoter was unmethylated in the developing testis and ovary, whereas it was hypermethylated in tissues that do not express SF1. Together these results indicate that the DNA methylation pattern is established early in the embryo and stably inherited thereafter throughout development to confine SF1 expression to the appropriate tissues. Chromatin immunoprecipitation analyses revealed that the transcriptional activator upstream stimulatory factor 2 and RNA polymerase II were specifically recruited to this DNA region in cells in which the proximal promoter is hypomethylated, providing functional support for the fact that lack of methylation corresponds to a transcriptionally active gene. In conclusion, we identified a region within the SF1/Sf1 gene that epigenetically directs cell-specific expression of SF1.

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46

Lavender, P., A. J. L. Clark, G. M. Besser, and L. H. Rees. "Variable methylation of the 5′-flanking DNA of the human pro-opiomelanocortin gene." Journal of Molecular Endocrinology 6, no. 1 (February 1991): 53–61. http://dx.doi.org/10.1677/jme.0.0060053.

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ABSTRACT The pro-opiomelanocortin gene is widely expressed in human tissues, although both transcriptional initiation sites and regulation appear to be tissue specific. In order to determine how promoter and enhancer choice is effected, we have studied the methylation pattern of the gene in a number of normal tissues, tumours and cell lines. Variability of this pattern was observed in the 5′-flanking DNA, particularly at the HpaII site located at −304 bp upstream from the pituitary CAP site. This site was generally methylated in tissues likely to express the predominant extrapituitary (800 nucleotide) message, while in tissues known to express the normal pituitary (1150 nucleotide) message and longer species, a tendency towards undermethylation was observed. Although the sites at which variable methylation occurs did not correspond to established binding sites for regulatory proteins, many of these regions remain to be determined and thus it is possible that methylation may be influential in the tissue-specific regulation of this gene.

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Shao-Qing, Tang, Zhang Yuan, Xu Qing, Sun Dong-Xiao, and Yu Ying. "Comparison of methylation level of genomes among different animal species and various tissues." Chinese Journal of Agricultural Biotechnology 4, no. 1 (April 2007): 75–79. http://dx.doi.org/10.1017/s1479236207001179.

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AbstractThe methylation levels of genomes were compared in swine, cattle, sheep, rat, chicken and duck, using the methylation-sensitive amplification polymorphism technique (MSAP). The results showed that the methylation levels in genomes of the species investigated were mostly about 40–50% (except cattle); the methylation level varied in different species; the methylation pattern in various tissues of each species was specific; for the same species, the methylation level of the tissue genome was mostly higher than that of the blood genome; the difference of methylation level between birds and mammals was not significant, however mammals appeared to have a lower hemi-methylation frequency and higher full methylation frequency than birds.

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Cho, Jae-Hyeon, Hiromichi Kimura, Tatsuya Minami, Jun Ohgane, Naka Hattori, Satoshi Tanaka, and Kunio Shiota. "DNA Methylation Regulates Placental Lactogen I Gene Expression." Endocrinology 142, no. 8 (August 1, 2001): 3389–96. http://dx.doi.org/10.1210/endo.142.8.8347.

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Abstract Expression of rat placental lactogen I is specific to the placenta and never expressed in other tissues. To obtain insight into the mechanism of tissue-specific gene expression, we investigated the methylation status in 3.4 kb of the 5′-flanking region of the rat placental lactogen I gene. We found that the distal promoter region of the rat placental lactogen I gene had more potent promoter activity than that of the proximal area alone, which contains several possible cis-elements. Although there are only 17 CpGs in the promoter region, in vitro methylation of the reporter constructs caused severe suppression of reporter activity, and CpG sites in the placenta were more hypomethylated than other tissues. Coexpression of methyl-CpG-binding protein with reporter constructs elicited further suppression of the reporter activity, whereas treatment with trichostatin A, an inhibitor of histone deacetylase, reversed the suppression caused by methylation. Furthermore, treatment of rat placental lactogen I nonexpressing BRL cells with 5-aza-2′-deoxycytidine, an inhibitor of DNA methylation, or trichostatin A resulted in the de novo expression of rat placental lactogen I. These results provide evidence that change in DNA methylation is the fundamental mechanism regulating the tissue-specific expression of the rat placental lactogen I gene.

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Rai, Kunal, Lincoln D. Nadauld, Stephanie Chidester, Elizabeth J. Manos, Smitha R. James, Adam R. Karpf, Bradley R. Cairns, and David A. Jones. "Zebra Fish Dnmt1 and Suv39h1 Regulate Organ-Specific Terminal Differentiation during Development." Molecular and Cellular Biology 26, no. 19 (October 1, 2006): 7077–85. http://dx.doi.org/10.1128/mcb.00312-06.

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ABSTRACT DNA methylation and histone methylation are two key epigenetic modifications that help govern heterochromatin dynamics. The roles for these chromatin-modifying activities in directing tissue-specific development remain largely unknown. To address this issue, we examined the roles of DNA methyltransferase 1 (Dnmt1) and the H3K9 histone methyltransferase Suv39h1 in zebra fish development. Knockdown of Dnmt1 in zebra fish embryos caused defects in terminal differentiation of the intestine, exocrine pancreas, and retina. Interestingly, not all tissues required Dnmt1, as differentiation of the liver and endocrine pancreas appeared normal. Proper differentiation depended on Dnmt1 catalytic activity, as Dnmt1 morphants could be rescued by active zebra fish or human DNMT1 but not by catalytically inactive derivatives. Dnmt1 morphants exhibited dramatic reductions of both genomic cytosine methylation and genome-wide H3K9 trimethyl levels, leading us to investigate the overlap of in vivo functions of Dnmt1 and Suv39h1. Embryos lacking Suv39h1 had organ-specific terminal differentiation defects that produced largely phenocopies of Dnmt1 morphants but retained wild-type levels of DNA methylation. Remarkably, suv39h1 overexpression rescued markers of terminal differentiation in Dnmt1 morphants. Our results suggest that Dnmt1 activity helps direct histone methylation by Suv39h1 and that, together, Dnmt1 and Suv39h1 help guide the terminal differentiation of particular tissues.

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50

Sakamoto, A. "Tissue-specific imprinting of the G protein Gs is associated with tissue-specific differences in histone methylation." Human Molecular Genetics 13, no. 8 (February 19, 2004): 819–28. http://dx.doi.org/10.1093/hmg/ddh098.

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