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Related Concept Videos

Cis-regulatory Sequences02:02

Cis-regulatory Sequences

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Cis-regulatory sequences are short fragments of non-coding DNA that are present on the same chromosomes as the genes that they regulate. These fragments serve as binding sites for transcriptional regulators, proteins that are responsible for controlling gene transcription and differential gene expression across cell types in eukaryotes. Cis-regulatory sequences can be close to the gene of interest or thousands of bases away in the DNA sequence; however, those sequences that are further away are...
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Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
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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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Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome.  Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form...
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Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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MAPT expression is mediated by long-range interactions with cis-regulatory elements.

Brianne B Rogers1,2, Ashlyn G Anderson1, Shelby N Lauzon1

  • 1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.

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Summary

Researchers identified cis-regulatory elements controlling MAPT gene expression, crucial for understanding neurodegenerative diseases like tauopathies. Disrupting these elements may offer protection against Alzheimer's disease.

Keywords:
Alzheimer’s diseaseEnhancerGene regulationMAPTNeuron

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Tauopathies are neurodegenerative diseases linked to abnormal tau protein aggregates, encoded by the MAPT gene.
  • MAPT gene expression increases during neuronal differentiation, suggesting cell-type-specific transcriptional regulation.
  • Understanding MAPT regulation is key to identifying genetic risk factors for neurodegeneration.

Approach:

  • Employed HiC, Capture-C, and single-nucleus multiomics (RNA-seq+ATAC-seq) in human iPSC-derived NPCs and neurons.
  • Utilized bulk ATAC-seq and ChIP-seq for H3K27Ac and CTCF to map regulatory elements.
  • Assayed candidate cis-regulatory elements (cCREs) using luciferase assays and CRISPR interference (CRISPRi).

Key Points:

  • Nominated 94 cCREs for MAPT, including neuron-specific elements.
  • Eleven regions demonstrated enhancer activity in luciferase assays.
  • Five cCREs were confirmed essential for MAPT expression via CRISPRi and RNA-seq.

Conclusions:

  • Identified proximal and distal regulatory elements for MAPT, including novel regions.
  • Demonstrated that genetic variants in cCREs are depleted in Alzheimer's disease cases, suggesting a protective role.
  • Highlights the importance of detailed cis-regulatory element knowledge for understanding disease risk.