Abstract

Single-cell RNA-sequencing (scRNA-seq) is becoming a powerful tool to investigate monoallelic expression (MAE) in various developmental and pathological processes. However, our knowledge of MAE during hematopoiesis and leukemogenesis is limited. In this study, we conducted a systematic interrogation of MAEs in bone marrow mononuclear cells (BMMCs) at single-cell resolution to construct a MAE atlas of BMMCs. We identified 1,020 constitutive MAEs in BMMCs, which included imprinted genes such as MEG8, NAP1L5, and IRAIN. We classified the BMMCs into six cell types and identified 74 cell type specific MAEs including MTSS1, MOB1A, and TCF12. We further identified 114 random MAEs (rMAEs) at single-cell level, with 78.1% single-allele rMAE and 21.9% biallelic mosaic rMAE. Many MAEs identified in BMMCs have not been reported and are potentially hematopoietic specific, supporting MAEs are functional relevance. Comparison of BMMC samples from a leukemia patient with multiple clinical stages showed the fractions of constitutive MAE were correlated with fractions of leukemia cells in BMMCs. Further separation of the BMMCs into leukemia cells and normal cells showed that leukemia cells have much higher constitutive MAE and rMAEs than normal cells. We identified the leukemia cell-specific MAEs and relapsed leukemia cell-specific MAEs, which were enriched in immune-related functions. These results indicate MAE is prevalent and is an important gene regulation mechanism during hematopoiesis and leukemogenesis. As the first systematical interrogation of constitutive MAEs, cell type specific MAEs, and rMAEs during hematopoiesis and leukemogenesis, the study significantly increased our knowledge about the features and functions of MAEs.

Highlights

  • Mammalian genomes including human genome are diploid, with one haploid inherited from mother and the other inherited from father

  • Bone marrow mononuclear cells (BMMCs) were collected from a boy diagnosed with acute lymphoblastic leukemia (ALL) separately at four clinical time points, i.e., diagnosis, refractory, complete remission, and relapse

  • The bone marrow mononuclear cells (BMMCs) were obtained from a boy diagnosed with acute lymphoblastic leukemia (Qin et al, 2021)

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Summary

Introduction

Mammalian genomes including human genome are diploid, with one haploid inherited from mother and the other inherited from father. The constitutive MAEs such as genomic imprinting only account for a small fraction of total MAEs. Random MAEs (rMAEs), that stochastically determine one allele to be transcribed and lead to different cells of the organism expressing different alleles, are much prevalent (Gimelbrant et al, 2007; Deng et al, 2014; Reinius and Sandberg, 2015; Chess, 2016). In contrast to chromosome-wide rMAE caused by random X-chromosome inactivation, autosomal rMAE on immunoglobulins and odorant receptors has been well studied in the past decades (Pernis et al, 1965; Hozumi and Tonegawa, 1976; Chess et al, 1994). The genome-wide landscape of autosomal rMAE in hematopoiesis is largely unexplored

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