PMID- 35672450 OWN - NLM STAT- MEDLINE DCOM- 20220708 LR - 20221017 IS - 2092-6413 (Electronic) IS - 1226-3613 (Print) IS - 1226-3613 (Linking) VI - 54 IP - 6 DP - 2022 Jun TI - ARID1B, a molecular suppressor of erythropoiesis, is essential for the prevention of Monge's disease. PG - 777-787 LID - 10.1038/s12276-022-00769-1 [doi] AB - At high altitude Andean region, hypoxia-induced excessive erythrocytosis (EE) is the defining feature of Monge's disease or chronic mountain sickness (CMS). At the same altitude, resides a population that has developed adaptive mechanism(s) to constrain this hypoxic response (non-CMS). In this study, we utilized an in vitro induced pluripotent stem cell model system to study both populations using genomic and molecular approaches. Our whole genome analysis of the two groups identified differential SNPs between the CMS and non-CMS subjects in the ARID1B region. Under hypoxia, the expression levels of ARID1B significantly increased in the non-CMS cells but decreased in the CMS cells. At the molecular level, ARID1B knockdown (KD) in non-CMS cells increased the levels of the transcriptional regulator GATA1 by 3-fold and RBC levels by 100-fold under hypoxia. ARID1B KD in non-CMS cells led to increased proliferation and EPO sensitivity by lowering p53 levels and decreasing apoptosis through GATA1 mediation. Interestingly, under hypoxia ARID1B showed an epigenetic role, altering the chromatin states of erythroid genes. Indeed, combined Real-time PCR and ATAC-Seq results showed that ARID1B modulates the expression of GATA1 and p53 and chromatin accessibility at GATA1/p53 target genes. We conclude that ARID1B is a novel erythroid regulator under hypoxia that controls various aspects of erythropoiesis in high-altitude dwellers. CI - (c) 2022. The Author(s). FAU - Azad, Priti AU - Azad P AD - Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. FAU - Caldwell, Andrew B AU - Caldwell AB AD - Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. FAU - Ramachandran, Srinivasan AU - Ramachandran S AD - Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. FAU - Spann, Nathanael J AU - Spann NJ AD - Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. FAU - Akbari, Ali AU - Akbari A AD - Department of Genetics, Harvard Medical School, Boston, MA, USA. AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. FAU - Villafuerte, Francisco C AU - Villafuerte FC AD - Laboratorio de Fisiologia del Transporte de Oxigeno/Fisiologia Comparada, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano Heredia, Lima, 31, Peru. FAU - Bermudez, Daniela AU - Bermudez D AD - Laboratorio de Fisiologia del Transporte de Oxigeno/Fisiologia Comparada, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano Heredia, Lima, 31, Peru. FAU - Zhao, Helen AU - Zhao H AD - Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. FAU - Poulsen, Orit AU - Poulsen O AD - Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. FAU - Zhou, Dan AU - Zhou D AD - Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. FAU - Bafna, Vineet AU - Bafna V AD - Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA. FAU - Subramaniam, Shankar AU - Subramaniam S AD - Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. AD - Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. AD - Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA. AD - Department of Nanoengineering, University of California, San Diego, La Jolla, CA, USA. FAU - Haddad, Gabriel G AU - Haddad GG AD - Division of Respiratory Medicine, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. ghaddad@health.ucsd.edu. AD - Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. ghaddad@health.ucsd.edu. AD - Rady Children's Hospital, San Diego, CA, 92123, USA. ghaddad@health.ucsd.edu. LA - eng GR - R01 GM114362/GM/NIGMS NIH HHS/United States GR - R01 HL146530/HL/NHLBI NIH HHS/United States GR - S10 OD026929/OD/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220607 PL - United States TA - Exp Mol Med JT - Experimental & molecular medicine JID - 9607880 RN - 0 (ARID1B protein, human) RN - 0 (Chromatin) RN - 0 (DNA-Binding Proteins) RN - 0 (Transcription Factors) RN - 0 (Tumor Suppressor Protein p53) SB - IM MH - *Altitude Sickness/genetics/metabolism MH - Chromatin/genetics/metabolism MH - Chronic Disease MH - *DNA-Binding Proteins/genetics/metabolism MH - Erythropoiesis/genetics MH - Humans MH - Hypoxia/genetics/metabolism MH - *Transcription Factors/genetics/metabolism MH - Tumor Suppressor Protein p53/genetics PMC - PMC9256584 COIS- The authors declare no competing interests. EDAT- 2022/06/08 06:00 MHDA- 2022/07/09 06:00 PMCR- 2022/06/07 CRDT- 2022/06/07 23:27 PHST- 2021/09/29 00:00 [received] PHST- 2022/02/14 00:00 [accepted] PHST- 2022/01/10 00:00 [revised] PHST- 2022/06/08 06:00 [pubmed] PHST- 2022/07/09 06:00 [medline] PHST- 2022/06/07 23:27 [entrez] PHST- 2022/06/07 00:00 [pmc-release] AID - 10.1038/s12276-022-00769-1 [pii] AID - 769 [pii] AID - 10.1038/s12276-022-00769-1 [doi] PST - ppublish SO - Exp Mol Med. 2022 Jun;54(6):777-787. doi: 10.1038/s12276-022-00769-1. Epub 2022 Jun 7.