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 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.
Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
Priti
P
Azad
Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
Huiwen W
HW
Zhao
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
Pedro J
0000-0002-8794-2839
PJ
Cabrales
Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093.
Roy
R
Ronen
Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
Dan
D
Zhou
Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
Orit
O
Poulsen
Department of Neurology, New Mexico Health Enhancement and Marathon Clinics Research Foundation, Albuquerque, NM 87122.
Otto
0000-0003-4493-7658
O
Appenzeller
Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
Yu Hsin
YH
Hsiao
Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093.
Vineet
V
Bafna
Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093 ghaddad@ucsd.edu.|Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093.|Rady Children's Hospital, San Diego, CA 92123.
Gabriel G
GG
Haddad
D000328:Adult; D000532:Altitude Sickness / Q000150:complications / Q000378:metabolism*; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D017753:Ecosystem; D004912:Erythrocytes / Q000473:pathology; D041905:Erythroid Cells / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000150:complications*; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D011086:Polycythemia / Q000209:etiology* / Q000378:metabolism*; D055815:Young Adult; D051020:bcl-X Protein / Q000378:metabolism*
D016207:Cytokines; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D051020:bcl-X Protein; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases