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Reprogramming alters the gene expression in somatic cells, transforming them into induced pluripotent stem (iPS) cells over several generations. Scientists can reprogram cells by introducing genes for four transcription factors—Oct4, Sox2, Klf4, and c-Myc (OSKM) by viral or non-viral methods. These factors are also known as Yamanaka factors after Shinya Yamanaka, who first generated iPS cells using mouse skin cells. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012...
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Chromatin modification alters gene expression; therefore, scientists can add histone-modifying enzymes, histone variants, and chromatin remodeling complexes to somatic cells to aid reprogramming into pluripotent stem (iPS) cells.
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Nuclear reprogramming is the process of switching gene expression of one cell type to that of another cell type, usually from a differentiated cell state to an undifferentiated cell state. Differentiation occurs during processes such as development and morphogenesis, tissue regeneration, and malignancy. Cells can also be artificially induced to reprogram their gene expression by techniques such as nuclear transfer, induced pluripotency, and cell fusion. Such techniques have many applications in...
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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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Transient naive reprogramming corrects hiPS cells functionally and epigenetically.

Sam Buckberry1,2,3,4, Xiaodong Liu5,6,7,8,9,10,11, Daniel Poppe1,2

  • 1Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia.

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|August 16, 2023
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Summary
This summary is machine-generated.

Transient-naive-treatment (TNT) reprogramming corrects epigenetic memory and aberrations in human induced pluripotent stem cells (hiPS cells), making them more like human embryonic stem (hES) cells. This new method enhances hiPS cell differentiation for biomedical applications.

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Area of Science:

  • Epigenetics
  • Stem Cell Biology
  • Reprogramming Technologies

Background:

  • Human induced pluripotent stem cells (hiPS cells) undergo significant epigenome changes but retain differences from human embryonic stem (hES) cells.
  • These epigenetic discrepancies, including memory and aberrations, impact hiPS cell function, with underlying mechanisms largely unknown.

Purpose of the Study:

  • To characterize the emergence and persistence of epigenetic differences during hiPS cell reprogramming.
  • To develop a novel reprogramming strategy that emulates the embryonic epigenetic reset and corrects hiPS cell epigenetic defects.

Main Methods:

  • Genome-wide DNA methylation profiling during primed and naive reprogramming.
  • Development and application of a transient-naive-treatment (TNT) reprogramming strategy.
  • Isogenic system analysis to assess epigenetic correction and functional outcomes.

Main Results:

  • Reprogramming-induced epigenetic aberrations arise mid-primed reprogramming; DNA demethylation initiates early in naive reprogramming.
  • TNT reprogramming reconfigures cell of origin-dependent repressive chromatin (H3K9me3, lamin-B1, CpH methylation) to an hES cell-like state.
  • TNT-reprogrammed hiPS cells show corrected transposable element expression, improved gene expression, and enhanced differentiation efficiency compared to conventional hiPS cells.

Conclusions:

  • TNT reprogramming effectively corrects epigenetic memory and aberrations, yielding hiPS cells molecularly and functionally akin to hES cells.
  • This strategy does not disrupt genomic imprinting and improves differentiation across various cell types.
  • TNT reprogramming offers a potential new standard for biomedical and therapeutic applications and a tool for studying epigenetic memory.