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

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.

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“…This phenomenon may be due to mutations in regulatory elements or to epigenetic mechanisms. There may be preferential expression of one allele in some cells, with preferential expression of the other allele in other cells, or a failure of normal transition from mono‐ to bi‐allelic expression in all cells, in a phenomenon called “random monoallelic expression” that may lead to the establishment of clones within a cell lineage 32 . In its most extreme form, imbalance of expression at the chromosomal level arises from skewed X‐lyonization.…”

“…There may be preferential expression of one allele in some cells, with preferential expression of the other allele in other cells, or a failure of normal transition from mono-to bi-allelic expression in all cells, in a phenomenon called "random monoallelic expression" that may lead to the establishment of clones within a cell lineage. 32 In its most extreme form, imbalance of expression at the chromosomal level arises from skewed X-lyonization. In this latter event, rather than the normal, Mendelian susceptibility to mycobacterial disease (MSMD) with complex phenotype…”