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Search: WFRF:(Niroula Abhishek) > (2021) > Genome-wide associa...

  • Lopez de Lapuente Portilla, AitzkoaLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Stem Cell Center,Division of stem cell research,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments (author)

Genome-wide association study on 13,167 individuals identifies regulators of hematopoietic stem and progenitor cell levels in human blood

  • BookEnglish2021

Publisher, publication year, extent ...

  • Cold Spring Harbor Laboratory,2021

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:93260968-6731-4ef0-9c97-c4231df55ada
  • https://lup.lub.lu.se/record/93260968-6731-4ef0-9c97-c4231df55adaURI
  • https://doi.org/10.1101/2021.03.31.437808DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ovr swepub-publicationtype
  • Subject category:vet swepub-contenttype

Notes

  • Understanding how hematopoietic stem and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and stem cell transplantation. To date, HSPC regulation has been extensively studied in vitro and in animal models, but less is known about the mechanisms in vivo in humans. Here, in a genome-wide association study on 13,167 individuals, we identify 9 significant and 2 suggestive DNA sequence variants that influence HSPC (CD34+) levels in human blood. The identified loci associate with blood disorders, harbor known and novel HSPC genes, and affect gene expression in HSPCs. Interestingly, our strongest association maps to the PPM1H gene, encoding an evolutionarily conserved serine/threonine phosphatase never previously implicated in stem cell biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. By functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates a MYB transcription factor binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, rs772557-A selectively increases HSPC subpopulations in which the MYB site is active, and PPM1H shRNA- knockdown increased CD34+ and CD34+90+ cell proportions in umbilical cord blood cultures. Our findings represent the first large-scale association study on a stem cell trait, illuminating HSPC regulation in vivo in humans, and identifying PPM1H as a novel inhibition target that can potentially be utilized clinically to facilitate stem cell harvesting for transplantation.

Subject headings and genre

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  • Ekdahl, LudvigLund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)med-lue (author)
  • Cafaro, CaterinaLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)ca1036ca (author)
  • Ali, ZainLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups(Swepub:lu)za7147al (author)
  • Miharada, NatsumiLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups(Swepub:lu)med-nmh (author)
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  • Zemaitis, KristijonasLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Stem Cell Center,Division of stem cell research(Swepub:lu)kr3367ze (author)
  • Lamarca Arrizabalaga, AnttonLund University (author)
  • Thodberg, MalteLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups(Swepub:lu)ma5728th (author)
  • Pertesi, MaroulioLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)ma6865pe (author)
  • Dhapola, ParasharLund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cells and Leukemia,Forskargrupper vid Lunds universitet,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups(Swepub:lu)pa1204dh (author)
  • Bao, Erik LHarvard Medical School,Broad Institute (author)
  • Niroula, AbhishekLund University,Lunds universitet,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Broad Institute(Swepub:lu)med-anu (author)
  • Bali, DivyaLund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Clinical Memory Research,Lund University Research Groups,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)di3408ba (author)
  • Norddahl, Gudmundur L.deCODE Genetics (author)
  • Ugidos Damboriena, NereaLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups(Swepub:lu)ne7857da (author)
  • Sankaran, Vijay GBroad Institute,Boston Children's Hospital (author)
  • Karlsson, GöranLund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cells and Leukemia,Forskargrupper vid Lunds universitet,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups(Swepub:lu)molm-gka (author)
  • Thorsteinsdottir, UnnurdeCODE Genetics (author)
  • Larsson, JonasLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,WCMM- Wallenberg center för molekylär medicinsk forskning,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,WCMM-Wallenberg Centre for Molecular Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)molm-jla (author)
  • Stefánsson, KárideCODE Genetics (author)
  • Nilsson, BjörnLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)klin-bni (author)
  • Avdelningen för hematologi och transfusionsmedicinInstitutionen för laboratoriemedicin (creator_code:org_t)

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