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Epigenetic profile for PRKN/PARK2 shows tissue-specific regulatory chromatin at the 5′-and 3′ ends of this 1.38-Mb gene. (A) The entire PRKN gene and part of the 5′ overlapping PACRG gene (chr6:161,720,965-163,176,926) with chromatin state and RNA-seq tracks. Purple or orange lines beneath the gene structure, regions amplified in the lower panels. (B-E) Left side, 3′ end (156
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Striated muscle has especially large energy demands. We identified 97 genes preferentially expressed in skeletal muscle and heart, but not in aorta, and found significant enrichment for mitochondrial associations among them. We compared the epigenomic and transcriptomic profiles of the 27 genes associated with striated muscle and mitochondria. Many...
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... had ~200-fold more expression of CKMT2 than myoblasts with parallel increases in promoter and enhancer chromatin ( Figure 5; Table S4). Figure 6) is an unusually large gene that codes for an E3 ubiquitin ligase (Parkin), which plays a major role in mitochondrial quality control as well as other regulatory roles [41]. Recessive loss-offunction mutations in this gene cause a juvenile form of Parkinson's disease, which results in abnormal mitochondrial function in the substantia nigra, in skeletal muscle, and in platelets [10]. ...
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... loss-offunction mutations in this gene cause a juvenile form of Parkinson's disease, which results in abnormal mitochondrial function in the substantia nigra, in skeletal muscle, and in platelets [10]. SkM and frontal cortex of brain were the tissues exhibiting the highest expression of this gene although their median expression levels were only TPM 9 and 8, respectively, and the gene is expressed in many other tissues ( Figure 6A). Given the modest levels of expression of PRKN in SkM and heart (Table 1) Figure 6B, right). ...
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... and frontal cortex of brain were the tissues exhibiting the highest expression of this gene although their median expression levels were only TPM 9 and 8, respectively, and the gene is expressed in many other tissues ( Figure 6A). Given the modest levels of expression of PRKN in SkM and heart (Table 1) Figure 6B, right). The epigenetic findings for myoblasts are consistent with their selective expression of this gene relative to heterologous cell cultures (Table S4). ) of PRKN (chr6:161,765,976-161,922,054); right side, 5′ end (31 kb) (chr6:163,125,655-163,157,029). ...
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... found that two regions of enhancer chromatin at the 3′ end of PRKN in myoblasts were associated with novel antisense (AS) intronic transcripts ( Figures 6E, boxes, and S5). Several polyadenylated AS transcripts from the distal end of the gene were indicated by the multiple promoter chromatin regions ( Figure 6B, left), strand-specific RNA-seq profiles ( Figure S5) and CAGE profiles (not shown). A myoblast-associated AS transcript aligned with the 15-kb myoblast-specific enhancer in this region (Figures 6B,E dotted boxes and S5). ...
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... myoblast-associated AS transcript aligned with the 15-kb myoblast-specific enhancer in this region (Figures 6B,E dotted boxes and S5). In addition, other AS transcripts were seen preferentially in both SkM and myoblasts that align with the myoblast/SkM enhancer/promoter region near the end of the gene (Figures 6B,E, black box and S5). Seven postnatal brain areas displayed enhancer and promoter chromatin similar to that of SkM. ...
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... shares a bidirectional promoter with the 59-kb PACRG (Parkin-coregulated gene) ( Figure 6A). Their TSS are only 0.2 kb apart. ...
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... related to PRKN is another striated muscle and mitochondria-associated gene VDAC1 (Voltage-Dependent Anion Channel 1; Figure S6). VDAC1 encodes a major component of the outer mitochondrial membrane and is a substrate for polyubiquitination by Parkin. ...
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... is required for Parkin's role in mitophagy in neural cells [42]. VDAC1 displayed more intragenic DHS, enhancer chromatin (a super-enhancer), and DNA hypomethylation in SkM and heart than did heterologous tissues, findings that are consistent with striated muscle displaying the highest expression of this gene ( Figure S6). ...
Citations
... In humans, cardiomyocyte development and myocardial infarction are both associated with an altered mitochondrial function [187,188]. In a study, it was discovered that the mitochondria-related genes in the cardiac cells in comparison to the other organs had different levels of methylation [189]. Numerous important processes, including ATP-dependent chromatin remodeling, are engaged in the epigenetic control of heart failure [190]. ...
Citation: Zare, A.; Salehpour, A.; Khoradmehr, A.; Bakhshalizadeh, S.; Najafzadeh, V.; Almasi-Turk, S.; Mahdipour, M.; Shirazi, R.; Tamadon, A. Epigenetic Modification Factors and microRNAs Network Associated with Differentiation of Embryonic Stem Cells and Induced Pluripotent Stem Cells toward Cardiomyocytes: A Review. Life 2023, 13, 569. https:// Abstract: More research is being conducted on myocardial cell treatments utilizing stem cell lines that can develop into cardiomyocytes. All of the forms of cardiac illnesses have shown to be quite amenable to treatments using embryonic (ESCs) and induced pluripotent stem cells (iPSCs). In the present study, we reviewed the differentiation of these cell types into cardiomyocytes from an epigenetic standpoint. We also provided a miRNA network that is devoted to the epigenetic commitment of stem cells toward cardiomyocyte cells and related diseases, such as congenital heart defects, comprehensively. Histone acetylation, methylation, DNA alterations, N6-methyladenosine (m 6 a) RNA methylation, and cardiac mitochondrial mutations are explored as potential tools for precise stem cell differentiation.
... One of the types of epigenomic studies that we have been involved in recently is the use of epigenomics to evaluate data from genome-wide association studies (GWAS), as described in the following section. Another is to examine epigenetic/transcription relationships using bioinformatics in comparisons of myoblasts (cultured muscle progenitor cells) and myotubes, their multinucleated differentiation products, to skeletal muscle tissue and to many other types of cell culture and tissue samples [3,[28][29][30][31]. We use databases for genetics, epigenomics and transcriptomics at the UCSC Genome Browser for the hg19 or hg38 reference human genomes. ...
... We do this using databases for methylomes (preferably WGBS), chromatin state and histone H3 lysine-27 acetylation (H3K27ac) profiles, open chromatin peak (DNaseI hypersensitivity) profiles and tissue and cell culture RNA-seq all available at UCSC Ge nome Browser Home and single-cell RNA-seq at The human cell types --The Human Protein Atlas. Some of our recent studies involve examining tissue-specific or disease-related DMRs, especially of functionally or genetically related groups of genes, in many different types of human samples and comparing DNA methylation profiles to chromatin epigenetic profiles and expression profiles of these genes and their neighboring genes [3,6,16,28,29]. We also use these kinds of data to identify transcription-regulatory regions that we subsequently test for methylationdependent regulatory function ( [7,32] and manuscripts in preparation). The results from our studies demonstrate how very informative it is to focus on individual genes and their neighborhoods at epigenomic databases to find exceptions to and often overlooked nuances of genomic trends in epigenetic/transcription associations. ...
Melanie Ehrlich, PhD, is a professor in the Tulane Cancer Center, the Tulane Center for Medical Bioinformatics and Genomics and the Hayward Human Genetics Program at Tulane Medical School, New Orleans, LA. She obtained her PhD in molecular biology in 1971 from the State University of New York at Stony Brook and completed postdoctoral research at Albert Einstein College of Medicine in 1972. She has been working on various aspects of epigenetics, starting with DNA methylation, since 1973. Her group made many first findings about DNA methylation (see below). For example, in 1982 and 1983, in collaboration with Charles Gehrke at the University of Missouri, she was the first to report tissue-specific and cancer-specific differences in overall DNA methylation in humans. In 1985, Xian-Yang Zhang and Richard Wang in her lab discovered a class of human DNA sequences specifically hypomethylated in sperm. In 1998, her group was the first to describe extensive losses of DNA methylation in pericentromeric and centromeric DNA repeats in human cancer. Her lab's many publications on the prevalence of both DNA hypermethylation and hypomethylation in the same cancers brought needed balance to our understanding of the epigenetics of cancer and to its clinical implications [ 1 ].
Besides working on cancer epigenetics, her research group has helped elucidate cytogenetic and gene expression abnormalities in the immunodeficiency, centromeric and facial anomalies (ICF) syndrome, a rare recessive disease often caused by mutations in DNMT3B. Her group also studied the epigenetics and transcriptomics of facioscapulohumeral muscular dystrophy (FSHD), whose disease locus is a tandem 3.3-kb repeat at subtelomeric 4q (that happens to be hypomethylated in ICF DNA [ 2 ]). Her study of FSHD has taken her in the direction of muscle (skeletal muscle, heart and aorta) epigenetics [ 3–6 ]. Recently, she has led research that applies epigenetics much more rigorously than usual to the evaluation of genetic variants from genome-wide association studies (GWAS) of osteoporosis and obesity. In continued collaboration with Sriharsa Pradhan at New England Biolabs and Michelle Lacey at Tulane University, she has compared 5-hydroxymethylcytosine and 5-methylcytosine clustering in various human tissues [ 7 ] and is studying myoblast methylomes that they generated by a new high-resolution enzymatic technique (enzymatic methyl-seq).
Sighthounds, a distinctive group of hounds comprising numerous breeds, have their origins rooted in ancient artificial selection of dogs. In this study, we performed genome sequencing for 123 sighthounds, including one breed from Africa, six breeds from Europe, two breeds from Russia and four breeds and 12 village dogs from the Middle East. We gathered public genome data of five sighthounds and 98 other dogs as well as 31 grey wolves to pinpoint the origin and genes influencing the morphology of the sighthound genome. Population genomic analysis suggested that sighthounds originated from native dogs independently and were comprehensively admixed among breeds, supporting the multiple origins hypothesis of sighthounds. An additional 67 published ancient wolf genomes were added for gene flow detection. Results showed dramatic admixture of ancient wolves in African sighthounds, even more than with modern wolves. Whole genome-scan analysis identified 17 positively selected genes (PSGs) in the African population, 27 PSGs in the European population, and 54 PSGs in the Middle Eastern population. None of the PSGs overlapped in the three populations. Pooled PSGs of the three populations were significantly enriched in "regulation of release of sequestered calcium ion into cytosol" (GO:0051279), which is related to blood circulation and heart contraction. In addition, ESR1, JAK2, ADRB1, PRKCE, and CAMK2D were under positive selection in all three selected groups. This suggests that different PSGs in the same pathway contributed to the similar phenotype of sighthounds. We identified an ESR1 mutation (chr1: g.42,177,149 T>C) in the transcription factor (TF) binding site of Stat5a, and a JAK2 mutation (chr1: g.93,277,007 T>A) in the TF binding site of Sox5. Functional experiments confirmed that the ESR1 and JAK2 mutation reduced their expression. Our results provide new insights into the domestication history and genomic basis of sighthounds.
