Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single cell resolution
- Universidad de Navarra, Spain
- Clinica Universidad de Navarra, Spain
- Hospital Universitario de Salamanca, Spain
- Vall d'Hebron Hospital Universitari, Spain
- NavarraBiomed, Spain
Abstract
Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single cell RNA sequencing (scRNAseq) to characterize an enriched population of human hematopoietic stem and progenitor cells (HSPCs) obtained from young and elderly healthy individuals. Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain age-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and gene regulatory networks (GRN) regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2 and RUNX1 suggesting a role of these TF in the pathogenesis of the disease. In summary, we demonstrate that the combination of single cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in complex biological systems such as early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with perturbations such as aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients.
Data availability
All the single cell RNA sequencing data is available at Gene Expression Omnibus under accession number GSE180298. The scripts needed to replicate the analysis are deposited on GitHub:https://github.com/mainciburu/scRNA-Hematopoiesis
-
Single-cell, multi-omic analysis identifies regulatory programs in mixed phenotype acute leukemiaNCBI Gene Expression Omnibus, GSE139369.
Article and author information
Author details
Tamara Jiménez Solas
Funding
Instituto de Salud Carlos III
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de Espinosa
- Mikel San Julian
- Tamara Jiménez Solas
- Felix Lopez
- Sandra Muntion
- Fermin Sanchez-Guijo
- Antonieta Molero
- Julia Montoro
- Guillermo Serrano
- Aintzane Diaz-Mazkiaran
- Miren Lasaga
- David Gomez-Cabrero
- Maria Diez-Campelo
- David Valcarcel
- Mikel Hernaez
- Juan Pablo Romero
- Felipe Prosper
Ministerio de Ciencia e Innovación (PhD fellowship FPU18/05488)
- Marina Ainciburu
Fundación Científica Asociación Española Contra el Cáncer (Investigador AECC award)
- Teresa Ezponda
H2020 Marie Skłodowska-Curie Actions (Grant Agreement No. 898356)
- Mikel Hernaez
Federación Española de Enfermedades Raras (PI17/00701,PI19/00726 and PI20/01308)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de Espinosa
- Mikel San Julian
- Tamara Jiménez Solas
- Felix Lopez
- Sandra Muntion
- Fermin Sanchez-Guijo
- Antonieta Molero
- Julia Montoro
- Guillermo Serrano
- Aintzane Diaz-Mazkiaran
- Miren Lasaga
- David Gomez-Cabrero
- Maria Diez-Campelo
- David Valcarcel
- Mikel Hernaez
- Juan Pablo Romero
- Felipe Prosper
Centro de Investigación Biomédica en Red de Cáncer (CB16/12/00489 and CB16/12/00225)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de Espinosa
- Mikel San Julian
- Tamara Jiménez Solas
- Felix Lopez
- Sandra Muntion
- Fermin Sanchez-Guijo
- Antonieta Molero
- Julia Montoro
- Guillermo Serrano
- Aintzane Diaz-Mazkiaran
- Miren Lasaga
- David Gomez-Cabrero
- Maria Diez-Campelo
- David Valcarcel
- Mikel Hernaez
- Juan Pablo Romero
- Felipe Prosper
Gobierno de Navarra (ERAPerMed MEET-AML 0011-2750-2019-000001; AGATA 0011-1411-2020-000010/0011-1411-2020-000011 and DIAN)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de Espinosa
- Mikel San Julian
- Tamara Jiménez Solas
- Felix Lopez
- Sandra Muntion
- Fermin Sanchez-Guijo
- Antonieta Molero
- Julia Montoro
- Guillermo Serrano
- Aintzane Diaz-Mazkiaran
- Miren Lasaga
- David Gomez-Cabrero
- Maria Diez-Campelo
- David Valcarcel
- Mikel Hernaez
- Juan Pablo Romero
- Felipe Prosper
la Caixa" Foundation " (GR-NET NORMAL-HIT HR20-00871)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de Espinosa
- Mikel San Julian
- Tamara Jiménez Solas
- Felix Lopez
- Sandra Muntion
- Fermin Sanchez-Guijo
- Antonieta Molero
- Julia Montoro
- Guillermo Serrano
- Aintzane Diaz-Mazkiaran
- Miren Lasaga
- David Gomez-Cabrero
- Maria Diez-Campelo
- David Valcarcel
- Mikel Hernaez
- Juan Pablo Romero
- Felipe Prosper
Cancer Research UK (C355/A26819)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de Espinosa
- Mikel San Julian
- Tamara Jiménez Solas
- Felix Lopez
- Sandra Muntion
- Fermin Sanchez-Guijo
- Antonieta Molero
- Julia Montoro
- Guillermo Serrano
- Aintzane Diaz-Mazkiaran
- Miren Lasaga
- David Gomez-Cabrero
- Maria Diez-Campelo
- David Valcarcel
- Mikel Hernaez
- Juan Pablo Romero
- Felipe Prosper
Fundación Científica Asociación Española Contra el Cáncer (Accelerator Award Program)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de Espinosa
- Mikel San Julian
- Tamara Jiménez Solas
- Felix Lopez
- Sandra Muntion
- Fermin Sanchez-Guijo
- Antonieta Molero
- Julia Montoro
- Guillermo Serrano
- Aintzane Diaz-Mazkiaran
- Miren Lasaga
- David Gomez-Cabrero
- Maria Diez-Campelo
- David Valcarcel
- Mikel Hernaez
- Juan Pablo Romero
- Felipe Prosper
Associazione Italiana per la Ricerca sul Cancro (Accelerator Award Program)
- Marina Ainciburu
- Teresa Ezponda
- Nerea Berastegui
- Ana Alfonso-Pierola
- Amaia Vilas-Zornoza
- Patxi San Martin-Uriz
- Diego Alignani
- Jose Lamo de Espinosa
- Mikel San Julian
- Tamara Jiménez Solas
- Felix Lopez
- Sandra Muntion
- Fermin Sanchez-Guijo
- Antonieta Molero
- Julia Montoro
- Guillermo Serrano
- Aintzane Diaz-Mazkiaran
- Miren Lasaga
- David Gomez-Cabrero
- Maria Diez-Campelo
- David Valcarcel
- Mikel Hernaez
- Juan Pablo Romero
- Felipe Prosper
Gobierno de Navarra (PhD fellowship 0011-0537-2019-000001)
- Nerea Berastegui
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jiwon Shim, Hanyang University, Republic of Korea
Ethics
Human subjects: The samples and data from the patients included in the study were provided by the Biobank of the University of Navarra and were processed according to standard operating procedures. Patients and healthy donors provided informed consent, together with consent for publication. The study was approved by the Clinical Research Ethics Committee of the Clinica Universidad de Navarra, following protocol # 2017.218.
Version history
- Preprint posted: July 31, 2021 (view preprint)
- Received: April 8, 2022
- Accepted: January 10, 2023
- Accepted Manuscript published: January 11, 2023 (version 1)
- Version of Record published: February 7, 2023 (version 2)
Copyright
© 2023, Ainciburu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,840
- views
-
- 467
- downloads
-
- 8
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single cell resolution
eLife 12:e79363.
https://doi.org/10.7554/eLife.79363
Further reading
-
- Computational and Systems Biology
Transcriptomic profiling became a standard approach to quantify a cell state, which led to accumulation of huge amount of public gene expression datasets. However, both reuse of these datasets or analysis of newly generated ones requires significant technical expertise. Here we present Phantasus - a user-friendly web-application for interactive gene expression analysis which provides a streamlined access to more than 96000 public gene expression datasets, as well as allows analysis of user-uploaded datasets. Phantasus integrates an intuitive and highly interactive JavaScript-based heatmap interface with an ability to run sophisticated R-based analysis methods. Overall Phantasus allows users to go all the way from loading, normalizing and filtering data to doing differential gene expression and downstream analysis. Phantasus can be accessed on-line at https://alserglab.wustl.edu/phantasus or can be installed locally from Bioconductor (https://bioconductor.org/packages/phantasus). Phantasus source code is available at https://github.com/ctlab/phantasus under MIT license.
-
- Computational and Systems Biology
- Evolutionary Biology
A comprehensive census of McrBC systems, among the most common forms of prokaryotic Type IV restriction systems, followed by phylogenetic analysis, reveals their enormous abundance in diverse prokaryotes and a plethora of genomic associations. We focus on a previously uncharacterized branch, which we denote coiled-coil nuclease tandems (CoCoNuTs) for their salient features: the presence of extensive coiled-coil structures and tandem nucleases. The CoCoNuTs alone show extraordinary variety, with three distinct types and multiple subtypes. All CoCoNuTs contain domains predicted to interact with translation system components, such as OB-folds resembling the SmpB protein that binds bacterial transfer-messenger RNA (tmRNA), YTH-like domains that might recognize methylated tmRNA, tRNA, or rRNA, and RNA-binding Hsp70 chaperone homologs, along with RNases, such as HEPN domains, all suggesting that the CoCoNuTs target RNA. Many CoCoNuTs might additionally target DNA, via McrC nuclease homologs. Additional restriction systems, such as Type I RM, BREX, and Druantia Type III, are frequently encoded in the same predicted superoperons. In many of these superoperons, CoCoNuTs are likely regulated by cyclic nucleotides, possibly, RNA fragments with cyclic termini, that bind associated CARF (CRISPR-Associated Rossmann Fold) domains. We hypothesize that the CoCoNuTs, together with the ancillary restriction factors, employ an echeloned defense strategy analogous to that of Type III CRISPR-Cas systems, in which an immune response eliminating virus DNA and/or RNA is launched first, but then, if it fails, an abortive infection response leading to PCD/dormancy via host RNA cleavage takes over.
