Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease

In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced plu...

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Published inThe Journal of experimental medicine Vol. 213; no. 12; pp. 2729 - 2744
Main Authors Azad, Priti, Zhao, Huiwen W., Cabrales, Pedro J., Ronen, Roy, Zhou, Dan, Poulsen, Orit, Appenzeller, Otto, Hsiao, Yu Hsin, Bafna, Vineet, Haddad, Gabriel G.
Format Journal Article
LanguageEnglish
Published United States The Rockefeller University Press 14.11.2016
Subjects
Adult
Altitude Sickness - complications
Altitude Sickness - metabolism
bcl-X Protein - metabolism
Cell Differentiation
Cell Hypoxia
Cell Line
Cysteine Endopeptidases - metabolism
Cytokines - metabolism
Ecosystem
Erythrocytes - pathology
Erythroid Cells - metabolism
GATA1 Transcription Factor - metabolism
Humans
Hypoxia - complications
Induced Pluripotent Stem Cells - metabolism
Polycythemia - etiology
Polycythemia - metabolism
Young Adult
Online AccessGet full text
ISSN0022-1007
1540-9538
1540-9538
DOI10.1084/jem.20151920

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Abstract In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.
AbstractList In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge's disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge's disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.
In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.
Azad and collaborators propose that Senp1 drives excessive erythropoiesis in high-altitude Andean dwellers suffering from chronic mountain sickness. In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge's disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.
Azad and collaborators propose that Senp1 drives excessive erythropoiesis in high-altitude Andean dwellers suffering from chronic mountain sickness. In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.
Author Poulsen, Orit
Appenzeller, Otto
Azad, Priti
Zhou, Dan
Ronen, Roy
Cabrales, Pedro J.
Zhao, Huiwen W.
Hsiao, Yu Hsin
Bafna, Vineet
Haddad, Gabriel G.
AuthorAffiliation 4 Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093
2 Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093
6 Department of Neurology, New Mexico Health Enhancement and Marathon Clinics Research Foundation, Albuquerque, NM 87122
7 Rady Children’s Hospital, San Diego, CA 92123
3 Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093
1 Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093
5 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093
AuthorAffiliation_xml – name: 6 Department of Neurology, New Mexico Health Enhancement and Marathon Clinics Research Foundation, Albuquerque, NM 87122
– name: 2 Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093
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– name: 1 Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093
– name: 3 Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093
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Snippet In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but...
In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge's disease) but...
Azad and collaborators propose that Senp1 drives excessive erythropoiesis in high-altitude Andean dwellers suffering from chronic mountain sickness. In this...
Azad and collaborators propose that Senp1 drives excessive erythropoiesis in high-altitude Andean dwellers suffering from chronic mountain sickness. In this...
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SubjectTerms Adult
Altitude Sickness - complications
Altitude Sickness - metabolism
bcl-X Protein - metabolism
Cell Differentiation
Cell Hypoxia
Cell Line
Cysteine Endopeptidases - metabolism
Cytokines - metabolism
Ecosystem
Erythrocytes - pathology
Erythroid Cells - metabolism
GATA1 Transcription Factor - metabolism
Humans
Hypoxia - complications
Induced Pluripotent Stem Cells - metabolism
Polycythemia - etiology
Polycythemia - metabolism
Young Adult
Title Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease
URI https://www.ncbi.nlm.nih.gov/pubmed/27821551
https://www.proquest.com/docview/1837287416
https://www.proquest.com/docview/1846394493
https://pubmed.ncbi.nlm.nih.gov/PMC5110013
Volume 213
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