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The long non-coding RNA Meg3 mediates imprinted gene expression during stem cell differentiation.

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The long non-coding RNA Meg3 is essential for repressing developmental genes Dlk1 and Rtl1 on the maternal chromosome. Meg3 also influences the three-dimensional genome structure, impacting gene regulation.

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Area of Science:

  • Genomics
  • Epigenetics
  • Developmental Biology

Background:

  • The Dlk1-Dio3 locus is imprinted, with key developmental genes silenced on the maternal chromosome.
  • The paternal allele expresses a polycistron including Meg3 long non-coding RNA (lncRNA), microRNAs, and snoRNAs.

Purpose of the Study:

  • To investigate the role of Meg3 lncRNA in the cis-regulation of imprinted genes within the Dlk1-Dio3 domain.
  • To determine if Meg3 lncRNA controls gene repression and influences chromatin structure.

Main Methods:

  • Generation of mouse embryonic stem cells (mESCs) with reduced polycistron RNA levels and Rian knockout.
  • CRISPR-mediated demethylation to achieve biallelic Meg3 expression.
  • Capture Hi-C to analyze Topologically Associating Domain (TAD) organization.

Main Results:

  • Meg3 lncRNA, but not Rian, is required for Dlk1 repression during ESC differentiation.
  • Biallelic Meg3 expression led to repression of Dlk1 and loss of Rtl1 expression.
  • Meg3 expression correlated with DNA hypomethylation, CTCF binding, and formation of a TAD linking Meg3 to Dlk1.

Conclusions:

  • Meg3 lncRNA plays a crucial role in repressing Dlk1 and Rtl1 on the maternal chromosome.
  • Meg3 is involved in establishing TAD structures that regulate gene expression within the Dlk1-Dio3 domain.
  • Aberrant MEG3 expression may contribute to human imprinting disorders.