Dataset Information

The pivotal and universal role of BGLT3 lncRNA in fetal globin gene expression

ABSTRACT: A highly selective and non-genotoxic G9a inhibitor, RK-701 was discovered, which upregulated the mRNA level of γ-globin but not β-globin both in human erythroid cells and in mice. Using RK-701, we examined the induction of the fetal (γ-) globin protein in human erythroid cells; HUDEP-2 and human CD34+ bone marrow and peripheral blood cells.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Erythrocyte, Cell Culture

DISEASE(S): Sickle Cell Anemia

SUBMITTER: Masaya Usui

LAB HEAD: Akihiro Ito

PROVIDER: PXD033536 | Pride | 2023-03-11

REPOSITORIES: Pride

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A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression.

Takase Shohei S Hiroyama Takashi T Shirai Fumiyuki F Maemoto Yuki Y Nakata Akiko A Arata Mayumi M Matsuoka Seiji S Sonoda Takeshi T Niwa Hideaki H Sato Shin S Umehara Takashi T Shirouzu Mikako M Nishigaya Yosuke Y Sumiya Tatsunobu T Hashimoto Noriaki N Namie Ryosuke R Usui Masaya M Ohishi Tomokazu T Ohba Shun-Ichi SI Kawada Manabu M Hayashi Yoshihiro Y Harada Hironori H Yamaguchi Tokio T Shinkai Yoichi Y Nakamura Yukio Y Yoshida Minoru M Ito Akihiro A

Nature communications 20230112 1

Sickle cell disease (SCD) is a heritable disorder caused by β-globin gene mutations. Induction of fetal γ-globin is an established therapeutic strategy. Recently, epigenetic modulators, including G9a inhibitors, have been proposed as therapeutic agents. However, the molecular mechanisms whereby these small molecules reactivate γ-globin remain unclear. Here we report the development of a highly selective and non-genotoxic G9a inhibitor, RK-701. RK-701 treatment induces fetal globin expression bot ...[more]

PMID: 36635268

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Project description:Background: Developmental stage-specific globin expression is a complex phenomenon that involves both trans- and cis-acting elements. While functional analyses ensuing recent genome-wide association studies have highlighted the important roles of trans-factors in regulating hemoglobin expression, these factors can not exert their functions without permissive chromatin domains. By transferring thoroughly profiled beta globin locus of undifferentiated human embryonic stem cells (hESCs) or hESC-derived erythroid cells into an adult erythroid transcriptional environment, we studied the influences of histone modifications on the globin expression decision within a fixed transcriptional environment. Shortly after the locus transfer, embryonic epsilon globin was not expressed regardless of original chromatin states, whereas fetal gamma globin was either expressed or not activated depending on original chromatin configurations, and the originally silent adult beta globin either remained silent or became activated depending on the expression status of gamma globin. These data suggest the interplay between transcriptional environment and the chromatin modifications determine the outcome of globin expression. As the ultimate silencing of gamma globin from hESC-derived erythroid cells in the adult transcriptional environment occurred after months-long cell proliferation, our work also has implications on attempts to generate beta globin expressing erythroid cells from hESCs or induced pluripotent stem cells. hESC line H1 (NIH code WA01, WiCell, Madison, WI) and adeno-associated virus (AAV)-targeted lines, were maintained and differentiated as previously described.12 (Details can be found in the supplemental information.) The expression of stem cell markers including SSEA-3, SSEA-4, TRA-1-60, and TRA-1-61 was detected by flow cytometry. To determine whether AAV-targeted lines retained their hematopoietic differentiation potential, confluent hESCs were harvested off the feeder layers and transferred to ultra-low attachment plates to allow for the formation of embryoid bodies (EBs). Day-14 EBs were dissociated into single cells and the expression of surface markers including CD34, CD71, CD45, CD31, CD41 and glycophorin-A was determined by flow cytometry. To induce erythroid differentiation, day-7 EBs were made into single cell suspension and cultured in erythroid-inducing medium for 14 days. Primers for real time PCR analysis of beta locus globin mRNA expression are provided in the supplemental information.

			Action	DRS
	210305_QE_18_152_Shirai_HUDEP_HbFI_2uL.raw	Raw
	F211363.dat	Other
	F211363.mgf	Mgf
	F211363.mzid.gz	Mzid