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Chromatin Position Affects Gene Expression02:35

Chromatin Position Affects Gene Expression

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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. 
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In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
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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.
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The process of chromosome duplication during cell division requires genome-wide disruption and re-assembly of chromatin. The chromatin structure must be accurately inherited, reassembled, and maintained in the daughter cells to ensure lineage propagation.
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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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Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
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Corticosteroid-induced chromatin loop dynamics at the FKBP5 gene.

Cheng Wang1, Freek Manders1,2, Laszlo Groh1,3

  • 1Department of Molecular Biology, Radboud Institute for Molecular Science, Faculty of Science, Radboud University, Nijmegen, The Netherlands.

Annals of the New York Academy of Sciences
|October 5, 2023
PubMed
Summary

The FKBP5 gene

Keywords:
FKBP5chromatin loopcorticosteroidepigeneticstopologically associated domain

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Area of Science:

  • Genomics
  • Epigenetics
  • Molecular Biology

Background:

  • FKBP5 is a glucocorticoid-inducible gene linked to psychiatric disorders.
  • Understanding its regulatory mechanisms is crucial for psychiatric research.

Purpose of the Study:

  • To investigate chromatin interaction frequencies within the FKBP5 topologically associated domain (TAD).
  • To elucidate the structural organization and regulatory elements of the FKBP5 locus.

Main Methods:

  • Employed 15 one-to-all chromatin capture viewpoints.
  • Analyzed gene promoters, enhancers, introns, and CTCF-loop anchors.

Main Results:

  • Identified a "one-TAD-one-gene" structure for FKBP5, with its promoter and enhancers within the TAD.
  • Discovered two nested CTCF loops coordinating the TAD, with loop extension linked to transcription.
  • FKBP5 TAD boundaries are resilient to stimulation and contain heterochromatin, while smaller genes are present.

Conclusions:

  • The FKBP5 TAD exhibits a stable, organized structure despite dynamic enhancer-promoter interactions.
  • Genetic and epigenetic variations influencing FKBP5 expression likely reside within a 240-kb region encompassing the TAD and its boundaries.