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Related Concept Videos

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...
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,...
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,...
Heterochromatin02:38

Heterochromatin

The extent of chromatin compaction can be studied by staining chromatin using specific DNA binding dyes. Under the microscope, the dense-compacted regions that take up more dye are called heterochromatin. Heterochromatin is further classified into two forms – constitutive heterochromatin and facultative heterochromatin.
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at 9th...
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...
Inheritance of Chromatin Structures03:17

Inheritance of Chromatin Structures

Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying DNA...

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Electrophoretic Analysis of Replication Through Structure-Prone DNA Repeats Within the SV40-Based Human Episome
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Histone deacetylase complexes promote trinucleotide repeat expansions.

Kim Debacker1, Aisling Frizzell, Olive Gleeson

  • 1Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.

Plos Biology
|February 25, 2012
PubMed
Summary

Specific histone deacetylase complexes (HDACs) actively promote DNA repeat expansions, which cause neurodegenerative diseases. Inhibiting these HDACs significantly suppressed expansions in yeast and human cells, offering a potential therapeutic strategy.

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Published on: November 30, 2018

Area of Science:

  • Genetics
  • Molecular Biology
  • Neuroscience

Background:

  • DNA trinucleotide repeat expansions are linked to over 17 inherited neurodegenerative diseases.
  • These expansions are actively promoted by cellular proteins, suggesting therapeutic targets.

Purpose of the Study:

  • To identify novel cellular factors that promote DNA repeat expansions.
  • To investigate the role of histone deacetylase complexes (HDACs) in promoting these expansions.

Main Methods:

  • Utilized budding yeast and cultured human astrocytes as model systems.
  • Employed gene mutation, knockdown, and inhibition strategies to study HDAC function.
  • Performed expansion assays and genetic analysis, including studies with nuclease mutants.

Main Results:

  • Specific histone deacetylase complexes (HDACs) were found to promote CTG•CAG repeat expansions.
  • Mutation or inhibition of yeast Rpd3L and Hda1 suppressed expansions by up to 90%.
  • HDAC3 inhibition/knockdown in human astrocytes suppressed expansions by 75%, while CBP/p300 inhibition stimulated them. HDACs were shown to act at a distance from the repeat, with Sae2 identified as a regulated factor.

Conclusions:

  • HDACs play a direct role in promoting DNA repeat expansions, establishing a causal link between HDACs and mutagenesis at specific DNA sequences.
  • HDAC3 inhibitors, currently explored for gene silencing, may also suppress somatic expansions contributing to disease progression.