Identification of a Novel Enhancer/Chromatin Opening Element Associated with High-Level <i>γ</i>-Globin Gene Expression

Shen, Yong; Bassett, Maclean; Gurumurthy, Aishwarya; Nar, Rukiye; Knudson, Isaac; Guy, Cameron R.; Perez, Alex; Mellen, Russell W.; Ikeda, Masatoshi; Hossain, Md. Abul; Huang, Suming; Igarashi, Kazuhiko; Bungert, Jörg

doi:10.1128/mcb.00197-18

Cited by 6 publications

(5 citation statements)

References 57 publications

(92 reference statements)

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“…These results are of interest because they support the hypothesis that LYAR is a major player in γ-globin gene regulation in β-thalassemia. Recently published studies have demonstrated that several transcription factors interact with several elements of the γ-globin gene promoter to control γ-globin gene expression in erythroid cells [9][10][11][12]. For instance, several of them (e.g., BCL11A) are (as LYAR) strong repressors of γ-globin gene transcription [17][18][19][20][21][22].…”

Section: Discussionmentioning

confidence: 99%

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Surface plasmon resonance based analysis of the binding of LYAR protein to the rs368698783 (G>A) polymorphic Aγ-globin gene sequences mutated in β-thalassemia

et al. 2019

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Recent studies have identified and characterized a novel putative transcriptional repressor site in a 5′ untranslated region of the Aγ-globin gene that interacts with the Ly-1 antibody reactive clone (LYAR) protein. LYAR binds the 5'-GGTTAT-3' site of the Aγ-globin gene, and this molecular interaction causes repression of gene transcription. In β-thalassemia patients, a polymorphism has been demonstrated (the rs368698783 G>A polymorphism) within the 5′-GGTTAT-3′ LYAR-binding site of the Aγ-globin gene. The major results gathered from surface plasmon resonance based biospecific interaction analysis (SPR-BIA) studies (using crude nuclear extracts, LYAR-enriched lysates, and recombinant LYAR) support the concept that the rs368698783 G>A polymorphism of the Aγ-globin gene attenuates the efficiency of LYAR binding to the LYAR-binding site. This conclusion was fully confirmed by a molecular docking analysis. This might lead to a very important difference in erythroid cells from β-thalassemia patients in respect to basal and induced levels of production of fetal hemoglobin. The novelty of the reported SPR-BIA method is that it allows the characterization and validation of the altered binding of a key nuclear factor (LYAR) to mutated LYAR-binding sites. These results, in addition to theoretical implications, should be considered of interest in applied pharmacology studies as a basis for the screening of drugs able to inhibit LYAR-DNA interactions. This might lead to the identification of molecules facilitating induced increase of γ-globin gene expression and fetal hemoglobin production in erythroid cells, which is associated with possible reduction of the clinical severity of the β-thalassemia phenotype.

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Section: Discussionmentioning

confidence: 99%

“…In this context, several transcription factors are known that interact with elements of the γ-globin gene promoter, thereby controlling γ-globin gene expression in erythroid cells [10][11][12][13][14][15][16][17][18]. Several of them (e.g., MYB and BCL11A) are strong repressors of γ-globin gene transcription [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Surface plasmon resonance based analysis of the binding of LYAR protein to the rs368698783 (G>A) polymorphic Aγ-globin gene sequences mutated in β-thalassemia

et al. 2019

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“…However, recruiting BAF to the enhancer regions did not significantly increase the expression of globin genes HBG1, HBE and HBB in either cell line (Supplemental figure 2A-B). In addition, further ChIP-sequencing analysis of Histone 3 lysine 4 monomethylation (H3K4me1) and Histone 3 lysine 27 acetylation (H3K27Ac), coupled with ATAC-sequencing and genomic perturbation studies have identified a locus within the BGLT3 gene and a locus 4-kilo base pairs upstream of the HBG promoter (HBG-4KBP) to be novel enhancers that regulate HBG1 expression [44][45][46] . We therefore designed sgRNAs to recruit BAF to these novel loci.…”

Section: Recruitment Of Baf To the Hbg1 Promoter Induces Gene And Pro...mentioning

confidence: 99%

Hijacking the transcriptional activation potential of the BAF complex via Induced Proximity

Chia,

Mayhew,

Sherbanee

et al. 2023

Preprint

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The BAF (Brg/Brahma-associated factors) complex, also referred to as the mammalian Switch/Sucrose-Nonfermentable (mSWI/SNF) chromatin remodeling complex, plays a pivotal role in epigenetically regulating diverse transcriptional programs. BAF’s chromatin remodeling activity, which enhances accessibility to transcriptional machinery, is critical for gene regulation. Recent studies have demonstrated that redirecting BAF complexes to bivalent promoters can alter the local epigenetic landscape, creating a permissive environment for transcription. As such, we hypothesize that redirecting BAF to “turn on” therapeutically relevant genes offers a potential approach for disease treatment.Using rapamycin as a chemical inducer of proximity (CIP) via CRISPR/Cas9 and FKBP/FRB dimerization, we redirected BAF complexes to the promoter of fetal hemoglobin (HBG), a therapeutic target for beta-globinopathies like sickle cell anemia and beta-thalassemia. This resulted in changes to the local chromatin and epigenetic landscapes, and increasedHBG1expression. Having confirmed BAF’s ability to activate gene expression, we then performed a genome-wide CRISPR activation drop-out screen to identify genes that when activated by BAF, suppress cellular proliferation. In addition to known tumor suppressors, our screen identified a number of genes with the ability to inhibit cell proliferation when activated by BAF. Collectively, our findings highlight the potential for harnessing the BAF’s intrinsic transcriptional activation capabilities for therapeutic purposes and lays the foundation for the potential development of therapeutics that function via induced proximity.

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“…Many datasets exploring erythroid and other hematopoietic cells have been uniformly processed and made publically available in the framework of the VISION project [13], which comprises over 200,000 candidate CREs, including almost all experimentally verified erythroid CREs. This and other databases (for example, the ENCODE project) are an extremely valuable resource for the discovery of new CREs, as exemplified by a newly found functional enhancer upstream of the Gg-globin gene [22].…”

Section: The Erythroid Chromatin Landscapementioning

confidence: 99%

‘Enhancing’ red cell fate through epigenetic mechanisms

Rossmann

Zon

2021

Current Opinion in Hematology

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Purpose of review Transcription of erythroid-specific genes is regulated by the three-dimensional (3D) structure and composition of chromatin, which dynamically changes during erythroid differentiation. Chromatin organization and dynamics are regulated by several epigenetic mechanisms involving DNA (de-)methylation, posttranslational modifications (PTMs) of histones, chromatin-associated structural proteins, and higher-order structural changes and interactions. This review addresses examples of recent developments in several areas delineating the interface of chromatin regulation and erythroid-specific lineage transcription. Recent findings We survey and discuss recent studies that focus on the erythroid chromatin landscape, erythroid enhancer-promotor interactions, super-enhancer functionality, the role of chromatin modifiers and epigenetic crosstalk, as well as the progress in mapping red blood cell (RBC) trait-associated genetic variants within cis-regulatory elements (CREs) identified in genome-wide association study (GWAS) efforts as a step toward determining their impact on erythroid-specific gene expression. Summary As one of the best characterized and accessible cell differentiation systems, erythropoiesis has been at the forefront of studies aiming to conceptualize how chromatin dynamics regulate transcription. New emerging technologies that bring a significantly enhanced spatial and temporal resolution of chromatin structure, and allow investigation of small cell numbers, have advanced our understanding of chromatin dynamics during erythroid differentiation in vivo.

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Identification of a Novel Enhancer/Chromatin Opening Element Associated with High-Level γ-Globin Gene Expression

Cited by 6 publications

References 57 publications

Surface plasmon resonance based analysis of the binding of LYAR protein to the rs368698783 (G>A) polymorphic Aγ-globin gene sequences mutated in β-thalassemia

Surface plasmon resonance based analysis of the binding of LYAR protein to the rs368698783 (G>A) polymorphic Aγ-globin gene sequences mutated in β-thalassemia

Hijacking the transcriptional activation potential of the BAF complex via Induced Proximity

‘Enhancing’ red cell fate through epigenetic mechanisms

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