EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression.

Blood
Aline RennevilleBenjamin L Ebert

Abstract

Fetal hemoglobin (HbF, α2γ2) induction is a well-validated strategy for sickle cell disease (SCD) treatment. Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression. EHMT1/2 catalyze mono- and dimethylation of lysine 9 on histone 3 (H3K9), raising the possibility that H3K9Me2, a repressive chromatin mark, plays a role in silencing γ-globin expression. In primary human adult erythroid cells, UNC0638 and EHMT1 or EHMT2 short hairpin RNA-mediated knockdown significantly increased γ-globin expression, HbF synthesis, and the percentage of cells expressing HbF. At effective concentrations, UNC0638 did not alter cell morphology, proliferation, or erythroid differentiation of primary human CD34(+) hematopoietic stem and progenitor cells in culture ex vivo. In murine erythroleukemia cells, UNC0638 and Ehmt2 CRISPR/Cas9-mediated knockout both led to a marked increase in expression of embryonic β-globin genes Hbb-εy and Hbb-βh1. In primary human adult erythroblasts, chromatin immunoprecipitation followed by sequencing analysis revealed that UNC0638 treatment leads to genome-wide depletion in H3K9Me2 and a concomitant increase in the activating m...Continue Reading

References

Feb 1, 1971·Proceedings of the National Academy of Sciences of the United States of America·C FriendT Sato
Jul 1, 1982·Proceedings of the National Academy of Sciences of the United States of America·J DeSimoneD Zwiers
Dec 9, 1982·The New England Journal of Medicine·T J LeyA W Nienhuis
Sep 11, 1997·The New England Journal of Medicine·H F Bunn
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Feb 10, 2007·Molecular Cell·Stefan KubicekThomas Jenuwein
Mar 28, 2008·The New England Journal of Medicine·Orah S Platt
Sep 2, 2008·Mutation Research·Christine M KieferAnn Dean
Sep 27, 2008·The EMBO Journal·Makoto TachibanaYoichi Shinkai
Dec 6, 2008·Nucleic Acids Research·Jong Kyong KimSriharsa Pradhan
Oct 14, 2009·Proceedings of the National Academy of Sciences of the United States of America·Chandra-Prakash ChaturvediMarjorie Brand
Jul 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·James E BradnerBenjamin L Ebert
Apr 19, 2011·Genes & Development·Yoichi Shinkai, Makoto Tachibana
Jul 12, 2011·Nature Chemical Biology·Masoud VedadiJian Jin
Sep 3, 2011·Blood·Marie-Catherine GiarratanaLuc Douay
Nov 1, 2012·Proceedings of the National Academy of Sciences of the United States of America·Chandra-Prakash ChaturvediMarjorie Brand
Dec 22, 2012·Epigenetics : Official Journal of the DNA Methylation Society·Shilpa Rani ShankarReshma Taneja
Apr 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jian XuStuart H Orkin
May 23, 2013·Blood·Margaret A Goodell, Lucy A Godley
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
Feb 18, 2014·Genes & Development·Bernhard LehnertzFabio M Rossi
Jul 30, 2014·Archives of Pharmacal Research·Jueng Soo You, Jeong Hwan Han
Sep 23, 2014·Epigenetics & Chromatin·Dustin E SchonesPatrick J Paddison
May 12, 2015·Nature Biotechnology·Junwei ShiChristopher R Vakoc

❮ Previous
Next ❯

Citations

Mar 18, 2016·ACS Medicinal Chemistry Letters·Robert A Copeland
Apr 8, 2016·Current Opinion in Hematology·Gregory J Kato
Apr 8, 2016·Blood·Matthew C Canver, Stuart H Orkin
Jun 3, 2016·Human Genetics·Ipek TasanHuimin Zhao
Jun 20, 2016·Current Opinion in Chemical Biology·Matthieu Schapira, Cheryl H Arrowsmith
Jun 25, 2016·Human Molecular Genetics·Elenoe C Smith, Stuart H Orkin
May 20, 2016·Proteomics. Clinical Applications·Raffaele Renella
Sep 14, 2016·British Journal of Haematology·Han Zhang, Nami McCarty
Jul 12, 2016·Acta Pharmacologica Sinica·Qing Liu, Ming-Wei Wang
Jan 13, 2017·Epigenetics : Official Journal of the DNA Methylation Society·Suzanne AcklooSusanne Müller
Apr 9, 2018·Biochemistry. Biokhimii︠a︡·O V IarovaiaS V Ulianov
Jan 31, 2018·International Journal of Hematology·Chingiz AsadovJeyhun Mammadov
Aug 3, 2016·Disease Models & Mechanisms·Namrata SinghMichael F Denny
Aug 2, 2018·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Angela RiversDonald Lavelle
Oct 10, 2019·Journal of Cellular Biochemistry·Monireh AjamiMasoud Soleimani
Mar 14, 2020·Current Opinion in Hematology·Lei YuJames D Engel
Dec 2, 2017·British Journal of Haematology·Divya S VinjamurStuart H Orkin
Nov 17, 2017·British Journal of Haematology·Alireza Paikari, Vivien A Sheehan
Feb 4, 2019·Molecular Diagnosis & Therapy·Eleni Katsantoni
Jun 23, 2020·Annals of Hematology·Tiwaporn NualkaewNatee Jearawiriyapaisarn
Nov 27, 2020·Journal of Clinical Medicine·Martin H Steinberg
Aug 19, 2020·Blood·Martin H Steinberg
Jan 21, 2021·British Journal of Haematology·Betty S PaceAbdullah Kutlar
Jan 30, 2021·Seminars in Hematology·Yu WangSharon A Singh
Oct 21, 2020·Molecular and Cellular Biology·Vigneshwaran VenkatesanSaravanabhavan Thangavel
Jul 1, 2018·Seminars in Hematology·Donald LavelleYogen Saunthararajah
Mar 19, 2021·American Journal of Human Genetics·Xiuqin BaoXiangmin Xu
Feb 26, 2021·Current Opinion in Hematology·Eugene Khandros, Gerd A Blobel
Aug 31, 2021·RSC Chemical Biology·Robert B A Quinlan, Paul E Brennan

❮ Previous
Next ❯

Related Concepts

Related Feeds

CRISPR (general)

Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). CRISPR-Cas system enables the editing of genes to create or correct mutations. Discover the latest research on CRISPR here.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.

Anti-Arrhythmic Drug Therapies

Anti-arrhythmic drugs are used to prevent abnormal heart rhythms. These medications are used in conditions including, ventricular tachycardia, ventricular fibrillation and atrial fibrillation. Discover the latest research on anti-arrhythmic drug therapies here.

Adult Stem Cells

Adult stem cells reside in unique niches that provide vital cues for their survival, self-renewal, and differentiation. They hold great promise for use in tissue repair and regeneration as a novel therapeutic strategies. Here is the latest research.

Anemia

Anemia develops when your blood lacks enough healthy red blood cells. Anemia of inflammation (AI, also called anemia of chronic disease) is a common, typically normocytic, normochromic anemia that is caused by an underlying inflammatory disease. Here is the latest research on anemia.

CRISPR for Genome Editing

Genome editing technologies enable the editing of genes to create or correct mutations. Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). Here is the latest research on the use of CRISPR-Cas system in gene editing.

CRISPR Ribonucleases Deactivation

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on mechanisms that underlie deactivation of CRISPR ribonucleases. Here is the latest research.