Abstract:Although DNA methylation is commonly invoked as a mechanism for transcriptional repression, the extent to which it actively silences transcription factor (TF) occupancy sites in vivo is unknown. To study the role of DNA methylation in the active modulation of TF binding, we quantified the effect of DNA methylation depletion on the genomic occupancy patterns of CTCF, an abundant TF with known methylation sensitivity that is capable of autonomous binding to its target sites in chromatin. Here, we show that the v… Show more
“…The ChIP-seq pileup plots indicate that constitutive CTCF binding sites display markedly higher occupancy signal than sites that are dynamically altered upon changes in cellular state. These results confirm and extend recent reports suggesting that there is a larger class of dynamically occupied CTCF sites than previously appreciated Maurano et al 2015).…”
Section: Ctcf Occupancy In Npcs Is Largely Preestablished In the Plursupporting
confidence: 82%
“…Cold Spring Harbor Laboratory Press on May 13, 2018 -Published by genome.cshlp.org Downloaded from of CTCF sites are dynamic across cellular states (Maurano et al 2015). Here, we find that CTCF occupancy is highest in the naïve pluripotent stem cell state and globally decreases in parallel with its expression during the commitment to multipotent NPCs.…”
Section: Wwwgenomeorgsupporting
confidence: 47%
“…Early studies comparing ChIP-seq signal between two or three cell types reported that CTCF binding was largely invariant, with 65%-90% of approximately 35,000 binding sites detected in all cellular states queried (Kim et al 2007;Cuddapah et al 2009). More recent studies comparing CTCF occupancy across 40 cell lines showed a range of 35,000-75,000 binding sites per cellular state, with a total of about 110,000 possible unique genomic locations (Maurano et al 2015). Notably, at most 20% of possible unique sites were classified as constitutive when comparing 40 cellular states, indicating that CTCF binding is more dynamic during development than previously reported (Wang et al 2012;Maurano et al 2015).…”
mentioning
confidence: 70%
“…More recent studies comparing CTCF occupancy across 40 cell lines showed a range of 35,000-75,000 binding sites per cellular state, with a total of about 110,000 possible unique genomic locations (Maurano et al 2015). Notably, at most 20% of possible unique sites were classified as constitutive when comparing 40 cellular states, indicating that CTCF binding is more dynamic during development than previously reported (Wang et al 2012;Maurano et al 2015). Thus, it is critically important to understand the dynamic patterns of CTCF binding and whether/how they are causally linked to chromatin architecture and gene expression during cellular state transitions in development.…”
mentioning
confidence: 99%
“…Genome-wide CTCF occupancy patterns have been mapped across more than 100 mammalian cell types (Kim et al 2007;Chen et al 2008;Cuddapah et al 2009;Wang et al 2012;Maurano et al 2015). Early studies comparing ChIP-seq signal between two or three cell types reported that CTCF binding was largely invariant, with 65%-90% of approximately 35,000 binding sites detected in all cellular states queried (Kim et al 2007;Cuddapah et al 2009).…”
CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naï ve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF, and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely preexisting in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of Yy1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a preexisting topological framework created by constitutive CTCF-mediated interactions.
“…The ChIP-seq pileup plots indicate that constitutive CTCF binding sites display markedly higher occupancy signal than sites that are dynamically altered upon changes in cellular state. These results confirm and extend recent reports suggesting that there is a larger class of dynamically occupied CTCF sites than previously appreciated Maurano et al 2015).…”
Section: Ctcf Occupancy In Npcs Is Largely Preestablished In the Plursupporting
confidence: 82%
“…Cold Spring Harbor Laboratory Press on May 13, 2018 -Published by genome.cshlp.org Downloaded from of CTCF sites are dynamic across cellular states (Maurano et al 2015). Here, we find that CTCF occupancy is highest in the naïve pluripotent stem cell state and globally decreases in parallel with its expression during the commitment to multipotent NPCs.…”
Section: Wwwgenomeorgsupporting
confidence: 47%
“…Early studies comparing ChIP-seq signal between two or three cell types reported that CTCF binding was largely invariant, with 65%-90% of approximately 35,000 binding sites detected in all cellular states queried (Kim et al 2007;Cuddapah et al 2009). More recent studies comparing CTCF occupancy across 40 cell lines showed a range of 35,000-75,000 binding sites per cellular state, with a total of about 110,000 possible unique genomic locations (Maurano et al 2015). Notably, at most 20% of possible unique sites were classified as constitutive when comparing 40 cellular states, indicating that CTCF binding is more dynamic during development than previously reported (Wang et al 2012;Maurano et al 2015).…”
mentioning
confidence: 70%
“…More recent studies comparing CTCF occupancy across 40 cell lines showed a range of 35,000-75,000 binding sites per cellular state, with a total of about 110,000 possible unique genomic locations (Maurano et al 2015). Notably, at most 20% of possible unique sites were classified as constitutive when comparing 40 cellular states, indicating that CTCF binding is more dynamic during development than previously reported (Wang et al 2012;Maurano et al 2015). Thus, it is critically important to understand the dynamic patterns of CTCF binding and whether/how they are causally linked to chromatin architecture and gene expression during cellular state transitions in development.…”
mentioning
confidence: 99%
“…Genome-wide CTCF occupancy patterns have been mapped across more than 100 mammalian cell types (Kim et al 2007;Chen et al 2008;Cuddapah et al 2009;Wang et al 2012;Maurano et al 2015). Early studies comparing ChIP-seq signal between two or three cell types reported that CTCF binding was largely invariant, with 65%-90% of approximately 35,000 binding sites detected in all cellular states queried (Kim et al 2007;Cuddapah et al 2009).…”
CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naï ve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF, and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely preexisting in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of Yy1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a preexisting topological framework created by constitutive CTCF-mediated interactions.
DNA methylation (5mC) is an essential epigenetic mark associated with transcriptional silencing. The role of 5mC in transcriptional repression is well established for a few hundred genes through methylation of their promoters. Yet, whether 5mC contributes more broadly to gene expression is an important open question. 5mC removal has recently been associated with the activation of enhancers, opening the possibility that 5mC may globally contribute to the expression of genes defining cell identities. Here, we will review the evidence and molecular mechanisms that link 5mC with the activity of enhancers. We will discuss the spread and amplitude of the potential gene expression changes controlled by 5mC at enhancers, and how these may contribute to the determination of cell identities during development.
Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407 TRIM27 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30-2.09, P = 4.52 9 10 À5), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87-1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407 TRIM27 methylation in NSCLC. LUSC patients had a higher average pack-year of smoking
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