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Chromatin Structure Regulates pre-mRNA Processing02:41

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Intact DNA strands can be found in fossils, while scientists sometimes struggle to keep RNA intact under laboratory conditions. The structural variations between RNA and DNA underlie the differences in their stability and longevity. Because DNA is double-stranded, it is inherently more stable. The single-stranded structure of RNA is less stable but also more flexible and can form weak internal bonds. Additionally, most RNAs in the cell are relatively short, while DNA can be up to 250 million...
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Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
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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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Methylated RNA Immunoprecipitation Assay to Study m5C Modification in Arabidopsis
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METTL3 shapes m6A epitranscriptomic landscape for successful human placentation.

Ram Parikshan Kumar1,2, Rajnish Kumar1, Avishek Ganguly1

  • 1Department of Pathology & Laboratory Medicine, University of Kansas Medical Center Kansas City, KS 66160, USA.

Biorxiv : the Preprint Server for Biology
|July 19, 2024
PubMed
Summary

Methyltransferase-like 3 (METTL3) is crucial for human placentation. Its balanced function in trophoblast cells is vital for pregnancy success, regulating cell renewal and differentiation.

Keywords:
Extravillus trophoblastMETTL3N6-methyladenosine (m6A)PlacentaRNA CUT&RUNSyncytiotrophoblastepitranscriptometrophoblast stem cells

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Area of Science:

  • Reproductive Biology
  • Epigenetics
  • Cell Biology

Background:

  • Methyltransferase-like 3 (METTL3) is essential for mammalian development.
  • The role of METTL3 in human placentation is largely unknown.
  • RNA m6A methylation is a key epitranscriptomic modification.

Purpose of the Study:

  • To investigate the role of METTL3 in human placentation.
  • To determine the impact of METTL3 dysregulation on pregnancy outcomes.
  • To elucidate the molecular mechanisms by which METTL3 influences trophoblast function.

Main Methods:

  • Analysis of METTL3 expression in human placental tissues from pregnancies with adverse outcomes.
  • Loss-of-function and gain-in-function studies in human trophoblast stem cells (TSCs).
  • Global RNA m6A profiling and RNA-binding analyses.
  • Conditional deletion of METTL3 in mouse trophoblast progenitors.

Main Results:

  • A balance of METTL3 in trophoblast cells is critical for successful human placentation.
  • Loss of METTL3 in trophoblast progenitors is linked to recurrent pregnancy loss and preterm birth.
  • METTL3 is upregulated in fetal growth restriction (FGR).
  • METTL3 is essential for TSC self-renewal and differentiation into extravillous trophoblast cells (EVTs).
  • METTL3 loss promotes syncytiotrophoblast (STB) development.
  • METTL3 regulates m6A modification of key trophoblast regulator mRNAs (e.g., GATA2, GATA3, TEAD1).
  • METTL3 deletion in mouse trophoblast progenitors arrests self-renewal.
  • METTL3 acts as a conserved epitranscriptomic governor in trophoblast progenitors.

Conclusions:

  • METTL3 plays a critical, conserved role in human placentation.
  • METTL3 regulates trophoblast progenitor self-renewal and differentiation fate.
  • Dysregulation of METTL3 contributes to adverse pregnancy outcomes.