---
title: "Perturb‑seq reveals co‑regulated gene programs governing hematopoietic stem and progenitor cells"
id: "biorxiv-16-perturb-seq-identifies-co-regulated-gene-programs-shaping-hematopoietic-stem"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-16-perturb-seq-identifies-co-regulated-gene-programs-shaping-hematopoietic-stem"
content_type: "clinical_feed_article"
specialty: "Hematology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.27.747033v1?rss=1"
published_at: "2026-08-29T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Perturb‑seq reveals co‑regulated gene programs governing hematopoietic stem and progenitor cells
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-16-perturb-seq-identifies-co-regulated-gene-programs-shaping-hematopoietic-stem
- **Specialty:** [Hematology](https://medichelpline.com/clinical-feed/hematology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.27.747033v1?rss=1)
- **Published At:** 2026-08-29T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study applied **Perturb-seq** with CRISPRi to primary mouse **hematopoietic stem and progenitor cells (HSPCs)** to map transcriptional consequences of genetic perturbations. 520 genes were targeted across the screen. - The authors developed an analytical workflow to disentangle perturbation-driven shifts in cell-state abundance and clonal heterogeneity from local, cell-state–specific transcriptional effects of each perturbation. - From these local perturbation signatures the team defined 19 **gene regulatory programs (GRPs)** based on co-regulation in response to perturbation rather than simple co-expression or manual curation. - The identified GRPs align with recognizable cell-biological processes such as cell cycle control, stress responses and lineage priming that are relevant to stem cell function. - Decomposition of independent gene expression datasets into GRP activity showed that program activity correlates with functional stem-cell phenotypes, including clonal output after transplantation. - GRP activity also associated with clinical phenotypes in retrospective acute myeloid leukemia (**AML**) cohorts, including survival and drug response, indicating potential translational relevance. - The work positions perturbation-derived co-regulation programs as an interpretable framework linking genetic regulators, cell-biological processes and stem-cell-associated phenotypes. - Data and code supporting the study are made available through figshare links and a GitHub repository (veltenlab/hsc19).
## Clinical Analysis & Structured Key Points
Perturb-seq identifies co-regulated gene programs shaping hematopoietic stem and progenitor cell function | bioRxiv Skip to main content New Results Perturb-seq identifies co-regulated gene programs shaping hematopoietic stem and progenitor cell function View ORCID Profile Joseph S Bowness , View ORCID Profile Aina Bernal Martinez , View ORCID Profile Jan Barinka , View ORCID Profile Jonas Schulte-Schrepping , View ORCID Profile Simon Renders , View ORCID Profile Alexander Waclawiczek , View ORCID Profile Aino-Maija Leppa , View ORCID Profile Andreas Trumpp , View ORCID Profile Simon Raffel , View ORCID Profile Simon Haas , View ORCID Profile Lars Velten doi: https://doi.org/10.64898/2026.08.27.747033 Joseph S Bowness 1 Computational Biology and Health Genomics, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Joseph S Bowness Aina Bernal Martinez 1 Computational Biology and Health Genomics, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Aina Bernal Martinez Jan Barinka 2 Berlin Institute of Health (BIH) at Charite Universitatsmedizin Berlin, Berlin, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jan Barinka Jonas Schulte-Schrepping 3 Systems Medicine, Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jonas Schulte-Schrepping Simon Renders 4 Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Simon Renders Alexander Waclawiczek 5 Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Alexander Waclawiczek Aino-Maija Leppa 5 Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Aino-Maija Leppa Andreas Trumpp 5 Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Andreas Trumpp Simon Raffel 4 Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Simon Raffel Simon Haas 2 Berlin Institute of Health (BIH) at Charite Universitatsmedizin Berlin, Berlin, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Simon Haas Lars Velten 1 Computational Biology and Health Genomics, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Lars Velten For correspondence: lars.velten{at}crg.eu Abstract Info/History Metrics Supplementary material Data/Code Preview PDF Abstract To sustain blood formation, hematopoietic stem and progenitor cells (HSPCs) coordinate a multitude of cell biological processes, from cell cycle control and stress responses to lineage priming. While many genetic regulators of high-level HSPC function have been identified, how HSPCs coordinate more basal cell biological programs, and how such programs relate to stem cell function, remains incompletely understood. Here we use Perturb-seq to profile the transcriptional consequences of targeting 520 genes by CRISPRi in primary mouse HSPC cultures. We developed an analytical strategy to separate perturbation-induced changes in cell-state abundance and clonal heterogeneity from cell-state-local transcriptional effects. From these local perturbation signatures, we identified 19 gene regulatory programs (GRPs) that are defined by co-regulation in response to genetic perturbation, in contrast to co-expression or human curation, and align well with cell biological processes. By decomposing gene expression data from functional and clinical studies into program activity, we show that GRP activities associate with, and predict, phenotypes such as clonal output after transplantation, as well as survival and drug response in retrospective acute myeloid leukemia (AML) cohorts. Together, our study establishes perturbation-derived co-regulation programs as an interpretable framework for linking genetic regulators, cell-biological processes and stem-cell-associated phenotypes. Competing Interest Statement The authors have declared no competing interest. Footnotes https://doi.org/10.6084/m9.figshare.31276981 https://doi.org/10.6084/m9.figshare.31277494 https://doi.org/10.6084/m9.figshare.32531301 https://github.com/veltenlab/hsc19 Funder Information Declared European Union Horizon Europe , 101041399 (ERC-StG AI4SYN to L.V.) Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Back to top Previous Next Posted August 29, 2026. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Perturb-seq identifies co-regulated gene programs shaping hematopoietic stem and progenitor cell function Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Perturb-seq identifies co-regulated gene programs shaping hematopoietic stem and progenitor cell function Joseph S Bowness , Aina Bernal Martinez , Jan Barinka , Jonas Schulte-Schrepping , Simon Renders , Alexander Waclawiczek , Aino-Maija Leppa , Andreas Trumpp , Simon Raffel , Simon Haas , Lars Velten bioRxiv 2026.08.27.747033; doi: https://doi.org/10.64898/2026.08.27.747033 Share This Article: Copy Citation Tools Perturb-seq identifies co-regulated gene programs shaping hematopoietic stem and progenitor cell function Joseph S Bowness , Aina Bernal Martinez , Jan Barinka , Jonas Schulte-Schrepping , Simon Renders , Alexander Waclawiczek , Aino-Maija Leppa , Andreas Trumpp , Simon Raffel , Simon Haas , Lars Velten bioRxiv 2026.08.27.747033; doi: https://doi.org/10.64898/2026.08.27.747033 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Genomics Subject Areas All Articles Animal Behavior and Cognition (7945) Biochemistry (18565) Bioengineering (14718) Bioinformatics (43981) Biophysics (22375) Cancer Biology (19499) Cell Biology (26670) Clinical Trials (138) Developmental Biology (13855) Ecology (20805) Epidemiology (2067) Evolutionary Biology (25250) Genetics (16067) Genomics (23351) Immunology (18528) Microbiology (42092) Molecular Biology (17885) Neuroscience (92579) Paleontology (691) Pathology (2958) Pharmacology and Toxicology (5051) Physiology (8029) Plant Biology (15846) Scientific Communication and Education (2090) Synthetic Biology (4523) Systems Biology (10156) Zoology (2368)
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