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Related Concept Videos

General Transcription Factors01:30

General Transcription Factors

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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Regulation of Expression at Multiple Steps01:23

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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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Transcription Factors02:16

Transcription Factors

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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Translation01:31

Translation

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Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
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Chromatin Structure Regulates pre-mRNA Processing02:41

Chromatin Structure Regulates pre-mRNA Processing

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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.
The chromatin structure, especially...
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RNA Splicing01:32

RNA Splicing

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Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
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Updated: Jul 4, 2025

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.

Sissy Bassani1, Jacqueline Chrast1, Giovanna Ambrosini2,3

  • 1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Medrxiv : the Preprint Server for Health Sciences
|January 31, 2024
PubMed
Summary

Minute changes in AFF3 gene function cause KINSSHIP syndrome, leading to intellectual disability and developmental issues. Both loss-of-function and dominant-negative variants in AFF3 are detrimental, impacting gene expression and cellular pathways.

Keywords:
exomehorseshoe kidneyintellectual disabilitymesomelic dysplasiatranscriptome

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Area of Science:

  • Genetics and Molecular Biology
  • Developmental Biology
  • Human Genetics

Background:

  • The KINSSHIP syndrome, characterized by intellectual disability, mesomelic dysplasia, and horseshoe kidney, is linked to de novo variants in the AFF3 gene.
  • Previous studies suggested a dominant-negative (DN) mechanism where increased AFF3 levels cause pathology, supported by mouse and zebrafish models.

Approach:

  • Screened intellectual disability cohorts for deleterious AFF3 variants.
  • Utilized animal (zebrafish) and cellular models to assess variant deleteriousness.
  • Analyzed transcriptomes of fibroblasts from affected individuals and engineered cell lines with varying AFF3 genotypes (+/+, DN/DN, LoF/+, LoF/LoF, DN/LoF).

Key Points:

  • Identified a KINSSHIP-like case with AFF3 duplication, supporting increased AFF3 levels as pathogenic.
  • Discovered milder syndromes linked to heterozygous loss-of-function (LoF) or biallelic missense AFF3 variants.
  • Homozygous LoF and compound heterozygous variants resulted in more severe phenotypes, consistent with semi-dominance.
  • Zebrafish models confirmed neurological defects from aff3 ablation, with some human missense variants failing to rescue.
  • Overexpression of mutated AFF3 in zebrafish embryos increased abnormal larvae.
  • AFF3 variants differentially modulate transcriptomes, affecting distinct pathways like DNA repair, with opposite effects observed between LoF and DN variants.

Conclusions:

  • Genetic variations in AFF3, even minor ones, can be deleterious.
  • The high pleiotropy associated with AFF3 variations underscores the critical role of precise AFF3 gene function in development.