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Forced Transdifferentiation

Forced Transdifferentiation

Transdifferentiation, also known as lineage reprogramming, was first discovered by Selman and Kafatos in 1974 in silkmoths. They observed that the moths’ cuticle-producing cells transformed into salt-producing cells. Many such cases of natural transdifferentiation occur in organisms. In humans, pancreatic alpha cells can become beta cells. In newts, the loss of the eye’s lens causes the pigmented epithelial cells to transdifferentiate into the lens cells.
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Related Experiment Video

Updated: Jun 18, 2025

Visualizing Genetic Variants, Short Targets, and Point Mutations in the Morphological Tissue Context with an RNA In Situ Hybridization Assay

Visualizing Genetic Variants, Short Targets, and Point Mutations in the Morphological Tissue Context with an RNA In Situ Hybridization Assay

Published on: August 14, 2018

RNA variant assessment using transactivation and transdifferentiation.

Emmylou C Nicolas-Martinez¹, Olivia Robinson¹, Christian Pflueger²

¹The Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia.

American Journal of Human Genetics

|July 31, 2024

Summary

This summary is machine-generated.

Researchers developed novel methods to activate "silent" Mendelian genes (SMGs) in cells, enabling RNA studies for variant classification and precision medicine. These techniques overcome limitations in studying genes with low expression in accessible tissues.

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Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation

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Published on: August 13, 2013

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Last Updated: Jun 18, 2025

Visualizing Genetic Variants, Short Targets, and Point Mutations in the Morphological Tissue Context with an RNA In Situ Hybridization Assay

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Published on: August 14, 2018

Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay EMSA and DNA-affinity Precipitation Assay DAPA

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Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation

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Published on: August 13, 2013

Area of Science:

Genomics
Molecular Biology
Genetic Medicine

Background:

Understanding splicing and nonsense variants' impact on RNA is vital for variant classification and precision medicine.
RNA studies using clinically accessible tissues (CATs) are key but limited by insufficient disease gene expression in 1,436 Mendelian disease genes (SMGs).
Neurological disorders account for the largest proportion (36%) of these silent Mendelian genes (SMGs).

Purpose of the Study:

To develop and validate methods for inducing expression of silent Mendelian genes (SMGs) in human dermal fibroblasts (HDFs).
To enable RNA-based investigations of variant impacts on SMGs for improved variant classification and precision medicine.
To apply these functional genomic solutions to study specific disease-associated genes (USH2A, SCN1A, DMD, PAK3).

Main Methods:

CRISPR-activation-based gene transactivation to induce SMG expression.
Fibroblast-to-neuron transdifferentiation to promote SMG expression.
Development of a highly multiplexed transactivation system and application of RNA sequencing (short- and long-read).

Main Results:

The multiplexed transactivation system induced expression of 20/20 (100%) tested SMGs in HDFs (6- to 90,000-fold induction).
Transdifferentiation of HDFs to neurons resulted in expression of 193/516 (37.4%) of neurologically implicated SMGs.
Induced SMG expression magnitude and isoform diversity were comparable to clinically relevant tissues.

Conclusions:

Transactivation and transdifferentiation are rapid, scalable functional genomic solutions for investigating SMG variants.
These methods overcome barriers in RNA-based variant impact studies, particularly for genes with low expression in accessible tissues.
The approaches facilitate variant classification and advance the suitability of precision medicine interventions.