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Random monoallelic gene expression increases upon embryonic stem cell differentiation.

Mélanie A Eckersley-Maslin1, David Thybert2, Jan H Bergmann3

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Random monoallelic gene expression increases during cell differentiation. Specific histone modifications mark active alleles, and some genes maintain expression levels through compensation.

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Area of Science:

  • Genetics
  • Developmental Biology
  • Epigenetics

Background:

  • Random autosomal monoallelic gene expression involves transcribing one of two homologous alleles.
  • Understanding the dynamics of this process during development is crucial for cell fate determination.

Purpose of the Study:

  • To investigate the dynamics of random monoallelic gene expression during cellular differentiation.
  • To identify genes exhibiting inheritable random monoallelic expression in embryonic stem cells and neural progenitor cells.
  • To explore epigenetic factors influencing allele-specific gene expression.

Main Methods:

  • Utilized allele-specific RNA-sequencing in clonal populations of hybrid mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs).
  • Analyzed DNA methylation, nuclear positioning, and histone modifications to differentiate active and inactive alleles.
  • Quantified the number of monoallelically expressed genes and compared expression levels between monoallelic and biallelic clones.

Main Results:

  • Identified 67 inheritable autosomal random monoallelically expressed genes in ESCs and 376 in NPCs, a 5.6-fold increase upon differentiation.
  • Found differential enrichment of specific histone modifications between active and inactive alleles, while DNA methylation and nuclear positioning did not distinguish them.
  • Observed that 8% of monoallelically expressed genes maintained similar expression levels between monoallelic and biallelic clones.

Conclusions:

  • Random monoallelic gene expression occurs stochastically during cell differentiation.
  • Specific histone modifications play a role in regulating allele-specific expression.
  • Cellular compensation mechanisms exist to maintain transcriptional output for some monoallelically expressed genes.