Abstract:Transcription factor SOX4 has been implicated in skeletal myoblast differentiation through the regulation of Cald1 gene expression; however, the detailed molecular mechanism underlying this process is largely unknown. Here, we demonstrate that SOX4 acetylation at lysine 95 by KAT5 (also known as Tip60) is essential for Cald1 promoter activity at the onset of C2C12 myoblast differentiation. KAT5 chromodomain was found to facilitate SOX4 recruitment to the Cald1 promoter, which is involved in chromatin remodelin… Show more
“…ARID5A , a regulator of the myotube BAF47 chromatin remodeling complex, is significantly upregulated at 8 hr (p = 7.2×10 −5 ) and may act to enhance MYOD1 binding to target promoters ( Joliot et al., 2014 ). NR4A3 , MEF2D , SIX4 , SIX1 , and SOX4 expression are also increased at 8 hr, all of which have important regulatory functions during differentiation in the myogenic lineage (see Figure 5 B) ( Ferrán et al., 2016 , Bentzinger et al., 2012 , Jang et al., 2015 ). Figure 5 Increased Genomic Contacts among Myogenic Regulatory Elements Set the Stage for Reprogramming (A) Early-phase expression dynamics of genes related to muscle cell terminal differentiation and chromatin remodeling.…”
SummaryGenome architecture has emerged as a critical element of transcriptional regulation, although its role in the control of cell identity is not well understood. Here we use transcription factor (TF)-mediated reprogramming to examine the interplay between genome architecture and transcriptional programs that transition cells into the myogenic identity. We recently developed new methods for evaluating the topological features of genome architecture based on network centrality. Through integrated analysis of these features of genome architecture and transcriptome dynamics during myogenic reprogramming of human fibroblasts we find that significant architectural reorganization precedes activation of a myogenic transcriptional program. This interplay sets the stage for a critical transition observed at several genomic scales reflecting definitive adoption of the myogenic phenotype. Subsequently, TFs within the myogenic transcriptional program participate in entrainment of biological rhythms. These findings reveal a role for topological features of genome architecture in the initiation of transcriptional programs during TF-mediated human cellular reprogramming.
“…ARID5A , a regulator of the myotube BAF47 chromatin remodeling complex, is significantly upregulated at 8 hr (p = 7.2×10 −5 ) and may act to enhance MYOD1 binding to target promoters ( Joliot et al., 2014 ). NR4A3 , MEF2D , SIX4 , SIX1 , and SOX4 expression are also increased at 8 hr, all of which have important regulatory functions during differentiation in the myogenic lineage (see Figure 5 B) ( Ferrán et al., 2016 , Bentzinger et al., 2012 , Jang et al., 2015 ). Figure 5 Increased Genomic Contacts among Myogenic Regulatory Elements Set the Stage for Reprogramming (A) Early-phase expression dynamics of genes related to muscle cell terminal differentiation and chromatin remodeling.…”
SummaryGenome architecture has emerged as a critical element of transcriptional regulation, although its role in the control of cell identity is not well understood. Here we use transcription factor (TF)-mediated reprogramming to examine the interplay between genome architecture and transcriptional programs that transition cells into the myogenic identity. We recently developed new methods for evaluating the topological features of genome architecture based on network centrality. Through integrated analysis of these features of genome architecture and transcriptome dynamics during myogenic reprogramming of human fibroblasts we find that significant architectural reorganization precedes activation of a myogenic transcriptional program. This interplay sets the stage for a critical transition observed at several genomic scales reflecting definitive adoption of the myogenic phenotype. Subsequently, TFs within the myogenic transcriptional program participate in entrainment of biological rhythms. These findings reveal a role for topological features of genome architecture in the initiation of transcriptional programs during TF-mediated human cellular reprogramming.
“…EDN3 (endothelin-3) was reported to be associated with enteric neuron development and blood circulation, thereby influencing the racing performance of Swedish-Norwegian coldblooded trotter horses [36]. KAT5 (histone acetyltransferase KAT5) chromodomain was found to facilitate SOX4 recruitment to the CALD1 (caldesmon 1) promoter to regulate skeletal myoblast differentiation [37]. As a core transcription factor in embryonic stem cells, ZNF281 (zinc finger protein 281) was found to be related to spontaneous osteochondrogenic differentiation [38].…”
As a nutrient sensor, the placenta plays a key role in regulating fetus growth and development. Long non-coding RNAs (lncRNAs) have been shown to regulate growth-related traits. However, the biological function of lncRNAs in horse placentas remains unclear. To compare the expression patterns of lncRNAs in the placentas of the Chinese Ningqiang (NQ) and Yili (YL) breeds, we performed a transcriptome analysis using RNA sequencing (RNA-seq) technology. NQ is a pony breed with an average adult height at the withers of less than 106 cm, whereas that of YL is around 148 cm. Based on 813 million high-quality reads and stringent quality control procedures, 3011 transcripts coding for 1464 placental lncRNAs were identified and mapped to the horse reference genome. We found 107 differentially expressed lncRNAs (DELs) between NQ and YL, including 68 up-regulated and 39 down-regulated DELs in YL. Six (TBX3, CACNA1F, EDN3, KAT5, ZNF281, TMED2, and TGFB1) out of the 233 genes targeted by DELs were identified as being involved in limb development, skeletal myoblast differentiation, and embryo development. Two DELs were predicted to target the TBX3 gene, which was found to be under strong selection and associated with small body size in the Chinese Debao pony breed. This finding suggests the potential functional significance of placental lncRNAs in regulating horse body size.
“…(Lysine acetyltransferase 5) 2.84 (0.03) Catalytic subunit of histone acetyltransferase complex which is involved in transcriptional activation of select genes, principally by acetylation of nucleosomal histones H4 and H2A [56].…”
Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial-mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism-epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.Cancers 2020, 12, 1031 2 of 25 cellular metabolic activity regulates transcriptional networks and cell-fate decisions via epigenetic programs involving metabolite-dependent effects on chromatin organization. Epigenetics refers to a change in chromatin that leads to the regulation of gene expression without alterations in the DNA sequence [6]. Epigenetic modifications include DNA methylation, and/or histone modifications by acetylation, ubiquitination, methylation, phosphorylation, sumoylation, glycosylation, and biotinylation, changes that play a critical role in many cellular processes [7][8][9][10][11][12][13]. The enzymes responsible for these modifications include histone acetyltransferases (HATs), histone deacetylases (HDACs), methyltransferases (KMTs), and demethylases (KDMs) [14][15][16].There is now an accumulation of evidence that the epigenome is sensitive to cellular metabolism and a link between metabolism and epigenetics [3][4][5][17][18][19] has been proposed, with epigenetics and gene transcription being influenced by products of metabolic pathways [...
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