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Related Concept Videos

Nucleosome Remodeling02:54

Nucleosome Remodeling

Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
Chromatin Position Affects Gene Expression02:35

Chromatin Position Affects Gene Expression

Chromatin is the massive complex of DNA and proteins packaged inside the nucleus. The complexity of chromatin folding and how it is packaged inside the nucleus greatly influences  access to genetic information. Generally, the nucleus' periphery is considered transcriptionally repressive, while the cell's interior is considered a transcriptionally active area. 
Topologically Associated Domains (TADs)
The 3-dimensional positioning of chromatin in the nucleus influences the timing and level of...
Spreading of Chromatin Modifications02:25

Spreading of Chromatin Modifications

The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
Writers
The writer is an enzyme that can...
The Nucleosome Core Particle01:12

The Nucleosome Core Particle

Nucleosomes are the DNA-histone complex, where the DNA strand is wound around the histone core. The histone core is an octamer containing two copies of H2A, H2B, H3, and H4 histone proteins.
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their primary aim is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. On the other hand, they must allow polymerase enzymes to access histone-bound DNA during...
The Nucleosome Core Particle02:10

The Nucleosome Core Particle

Nucleosomes are the DNA-histone complex, where the DNA strand is wound around the histone core. The histone core is an octamer containing two copies of H2A, H2B, H3, and H4 histone proteins.
The paradox
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their main responsibility is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. While on the other hand, they must allow polymerase enzymes to access DNA...
Histone Modification02:32

Histone Modification

The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...

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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
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Enhanced CRAd activity using enhancer motifs driven by a nucleosome positioning sequence.

Soraya Bravo1, Felipe Núñez, Fernando Cruzat

  • 1Centro de Investigaciones Biomédicas and FONDAP Center for Genome Regulation, Universidad Andres Bello, Santiago, Chile.

Molecular Therapy : the Journal of the American Society of Gene Therapy
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Nucleosome positioning sequences (NPS) enhance tumor-specific promoter activity and cancer-killing virus replication. This finding is crucial for developing novel gene therapies for cancer and other diseases.

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Area of Science:

  • Epigenetics
  • Virology
  • Gene Therapy

Background:

  • Cancer development is influenced by epigenetic changes, including nucleosome positioning.
  • Tumor-specific promoters (TSPs) are being explored to drive the replication of oncolytic viruses.
  • Conditionally replicative adenoviruses (CRAd) have shown therapeutic promise in clinical trials.

Purpose of the Study:

  • To investigate the impact of a nucleosome positioning sequence (NPS) combined with Wnt-responsive motifs (pART enhancer) on TSP transcriptional activity and CRAd lytic activity.
  • To determine the in vitro and in vivo efficacy of the pART enhancer in conjunction with a TSP.
  • To assess the role of NPS in enhancing promoter activity and CRAd antitumor efficacy.

Main Methods:

  • Constructing a pART enhancer with NPS upstream of the gastrointestinal cancer-specific REG1A promoter (REG1A-pr).
  • Evaluating the transcriptional activity of REG1A-pr with and without the pART enhancer in vitro.
  • Assessing the lytic activity of a CRAd driven by REG1A-pr with and without the pART enhancer.
  • Testing the in vivo antitumor efficacy of the CRAd in orthotopic pancreatic xenografts after deleting the NPS.
  • Examining the effect of NPS on other promoters and response elements (hypoxia, NFκB).

Main Results:

  • The pART enhancer significantly increased the transcriptional activity of the REG1A promoter.
  • The pART enhancer enhanced the in vitro lytic activity of the CRAd.
  • The enhancer's effect was strictly dependent on the presence of the NPS.
  • Deletion of the NPS severely impaired the in vivo antitumor efficacy of the CRAd.
  • The NPS enhanced the activity of other promoters and response elements.

Conclusions:

  • The combination of NPS and Wnt-responsive motifs (pART enhancer) effectively boosts TSP activity and CRAd replication.
  • NPS is critical for the in vitro and in vivo efficacy of CRAd-based cancer therapy.
  • NPS holds potential as a valuable tool for gene therapy applications in cancer and other diseases.