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Related Concept Videos

Histone Modification02:32

Histone Modification

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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...
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Riboswitches are non-coding mRNA domains that regulate the transcription and translation of downstream genes without the help of proteins. Riboswitches bind directly to a metabolite and can form unique stem-loop or hairpin structures in response to the amount of the metabolite present. They have two distinct regions – a metabolite-binding aptamer and an expression platform.
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Types of RNA

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Overview
Three main types of RNA are involved in protein synthesis: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). These RNAs perform diverse functions and can be broadly classified as protein-coding or non-coding RNA. Non-coding RNAs play important roles in the regulation of gene expression in response to developmental and environmental changes. Non-coding RNAs in prokaryotes can be manipulated to develop more effective antibacterial drugs for human or animal use.
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Spreading of Chromatin Modifications02:25

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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.
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Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

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Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
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Feedback Inhibition00:46

Feedback Inhibition

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Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
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Related Experiment Video

Updated: Jun 2, 2025

Analysis of Histone Antibody Specificity with Peptide Microarrays
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Analogue-Sensitive Inhibition of Histone Demethylases Uncovers Member-Specific Function in Ribosomal Protein

Jordan Kuwik1, Valerie Scott1, Sara Chedid1

  • 1Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.

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Researchers developed analogue-sensitive (as) KDM4 mutants for precise targeting. N-oxalyl leucine (NOL) selectively inhibited these mutants, revealing KDM4A

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Isolation and Cultivation of Neural Progenitors Followed by Chromatin-Immunoprecipitation of Histone 3 Lysine 79 Dimethylation Mark
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Isolation and Cultivation of Neural Progenitors Followed by Chromatin-Immunoprecipitation of Histone 3 Lysine 79 Dimethylation Mark

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Area of Science:

  • Biochemistry and Molecular Biology
  • Epigenetics and Gene Regulation
  • Chemical Biology and Drug Discovery

Background:

  • Lysine demethylases (KDMs) are crucial regulators of gene expression, utilizing iron and 2-oxoglutarate (2OG).
  • KDMs are significant drug targets for cancer therapy, but their functional diversity requires precise chemical probes.
  • Limited mechanistic understanding of human KDM heterogeneity hinders targeted therapeutic development.

Purpose of the Study:

  • To develop analogue-sensitive (as) mutants of KDM4 subfamily members for dissecting individual biological functions.
  • To create chemical probes for temporally controlled and specific inhibition of KDM4 activity.
  • To elucidate the role of specific KDM4 members, particularly KDM4A, in cellular processes and cancer.

Main Methods:

  • Engineering of KDM4 mutants by replacing active site phenylalanine with alanine, creating analogue-sensitive variants.
  • Development and application of cofactor-competitive inhibitors, such as N-oxalyl leucine (NOL), targeting the as-mutants.
  • Utilizing cell-permeable NOL prodrugs to inhibit as-KDMs in human cells and assess histone lysine methylation.
  • Conditional perturbation of orthogonal KDM enzymes to define member-specific functions.

Main Results:

  • Successfully generated KDM4 as-mutants with wild-type catalytic activity and substrate specificity.
  • Identified N-oxalyl leucine (NOL) as a potent and reversible inhibitor of KDM4 as-mutants with submicromolar efficacy.
  • Demonstrated NOL prodrugs' ability to modulate histone lysine methylation in cultured human cells.
  • Uncovered a KDM4A-specific role in promoting ribosomal protein synthesis via locus-specific histone demethylation.

Conclusions:

  • Analogue-sensitive KDM4 mutants and NOL inhibitors provide powerful tools for dissecting KDM functional heterogeneity.
  • KDM4A plays a critical role in regulating rRNA expression, ribosome assembly, and protein synthesis.
  • These findings offer mechanistic insights into KDM4A's contribution to cancers characterized by high proliferative rates.