In Vivo Clonal Analysis Reveals Random Monoallelic Expression in Lymphocytes That Traces Back to Hematopoietic Stem Cells

Nadiya Kubasova, Clara F. Alves-Pereira, Saumya Gupta, Svetlana Vinogradova, Alexander Gimelbrant, Vasco M. Barreto

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Abstract

Evaluating the epigenetic landscape in the stem cell compartment at the single-cell level is essential to assess the cells’ heterogeneity and predict their fate. Here, using a genome-wide transcriptomics approach in vivo, we evaluated the allelic expression imbalance in the progeny of single hematopoietic cells (HSCs) as a read-out of epigenetic marking. After 4 months of extensive proliferation and differentiation, we found that X-chromosome inactivation (XCI) is tightly maintained in all single-HSC derived hematopoietic cells. In contrast, the vast majority of the autosomal genes did not show clonal patterns of random monoallelic expression (RME). However, a persistent allele-specific autosomal transcription in HSCs and their progeny was found in a rare number of cases, none of which has been previously reported. These data show that: 1) XCI and RME in the autosomal chromosomes are driven by different mechanisms; 2) the previously reported high frequency of genes under RME in clones expanded in vitro (up to 15%) is not found in clones undergoing multiple differentiation steps in vivo; 3) prior to differentiation, HSCs have stable patterns of autosomal RME. We propose that most RME patterns in autosomal chromosomes are erased and established de novo during cell lineage differentiation.

Original languageEnglish
Article number827774
JournalFrontiers in Cell and Developmental Biology
Volume10
DOIs
Publication statusPublished - 8 Aug 2022

Keywords

  • allele-specific expression
  • allelic imbalance (AI)
  • clonal analysis
  • epigenetics
  • hematopoietic stem cell (HSC)
  • random monoallelic expression (RME)
  • RNA-seq
  • X-chromosome inactivation (XCI)

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