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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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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...
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Combinatorial Gene Control

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Combinatorial gene control is the synergistic action of several transcriptional factors to regulate the expression of a single gene. The absence of one or more of these factors may lead to a significant difference in the level of gene expression or repression.
The expression of more than 30,000 genes is controlled by approximately 2000-3000 transcription factors. This is possible because a single transcription factor can recognize more than one regulatory sequence. The specificity in gene...
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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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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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Pleiotropy

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Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
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Updated: Jun 21, 2025

Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
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Interface-guided phenotyping of coding variants in the transcription factor RUNX1.

Kivilcim Ozturk1, Rebecca Panwala2, Jeanna Sheen3

  • 1Division of Medical Genetics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA.

Cell Reports
|July 5, 2024
PubMed
Summary
This summary is machine-generated.

Interpreting RUNX1 mutations is difficult. Functional screening identified wild-type-like, loss-of-function, and hypomorphic variants, improving variant classification and understanding mutation impact.

Keywords:
CP: GenomicsCP: Molecular biologyPerturb-seqRNA-seqcancercoding variantinterfaceprotein-protein interactionsingle-celltranscription factor

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Area of Science:

  • Genomics
  • Molecular Biology
  • Cancer Research

Background:

  • Interpreting single-gene missense mutations, particularly in cancer-related genes like RUNX1, presents a significant challenge.
  • RUNX1 mutations are implicated in various hematological malignancies, but their precise functional consequences are often unclear.

Purpose of the Study:

  • To functionally characterize RUNX1 missense mutations using a scalable screening approach.
  • To categorize mutations based on their impact on cellular programs and downstream gene expression.
  • To improve the classification of variants of uncertain significance (VUS) in RUNX1.

Main Methods:

  • Deployment of scalable functional screening by sequencing (SEUSS), a Perturb-seq method, to introduce and assess 115 RUNX1 mutations.
  • Analysis of single-cell RNA sequencing profiles to categorize mutations into wild-type (WT)-like, loss-of-function (LoF)-like, and hypomorphic groups.
  • Orthogonal assays for validation of functional categories and computational classifier training for VUS prediction.

Main Results:

  • Identification of three distinct functional categories for RUNX1 mutations: WT-like, LoF-like, and hypomorphic.
  • LoF-like variants were enriched at the DNA-binding site and frequently recurrent in cancer, though recurrence did not solely predict function.
  • Hypomorphic variants influenced protein interactions, affecting gene expression related to nerve growth factor (NGF) response and neutrophil cytokine recruitment.
  • RUNX1-binding motifs were found in accessible DNA near differentially expressed genes.
  • Reclassification of 16 VUS and development of a classifier to predict the function of 103 additional variants.

Conclusions:

  • Scalable functional screening is effective for interpreting missense mutations in genes like RUNX1.
  • Mutation recurrence alone is insufficient for predicting functional impact; functional categorization is crucial.
  • Understanding the distinct functional impacts of LoF-like and hypomorphic variants provides insights into RUNX1-driven phenotypes.
  • Targeting protein interactions offers a promising avenue for defining the phenotypic landscape of missense mutations.