Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming

Sripichai, Orapan; Kiefer, Christine M.; Bhanu, Natarajan V.; Tanno, Toshihiko; Noh, Seung-Jae; Goh, Sung‐Ho; Russell, Janice; Rognerud, Cheryl L.; Ou, Ching-Nan; O'Neal, Patricia; Meier, Emily Riehm; Gantt, Nicole M.; Byrnes, Colleen; Lee, Y. Terry; Dean, Ann; Miller, Jeffery L.

doi:10.1182/blood-2009-05-219386

Cited by 49 publications

(53 citation statements)

References 43 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23 The strongest accumulation of H3K9me2 in the b-globin locus of adult erythroid cells was detected at the silenced g-globin genes in agreement with previous observations. 24 Higher H3K9me2 at the fetal compared with the adult genes was also reported in primary human bone marrow erythroblasts in the absence of ex vivo culture. 28 Inhibition of G9a methyltransferase activity caused a strong decrease of H3K9 dimethylation throughout the locus, but this was especially notable at the g-globin gene promoter associated with reactivation of g-globin gene expression, further supporting a repressive role for G9a in regulation of hemoglobin production.…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, the strongest (35-fold) decrease in H3K9me2 was observed at the activated g-globin gene promoters, consistent with the absence of this mark at active human fetal globin genes. 24 Additionally, H3K27me2 distribution was investigated because it has been reported to serve a repressive role with respect to ey-globin expression in mouse MEL cells, which is relieved by G9a reduction. 9 H3K27me2 was reduced across the locus in UNC0638-treated cells but to a more modest extent than for H3K9me2 and can still be detected at the g-globin promoter ( Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping

Krivega¹,

Byrnes

Vasconcellos

et al. 2015

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping

Krivega¹,

Byrnes

Vasconcellos

et al. 2015

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…Quantitative real-time PCR amplification was carried out in a 7900HT Fast Real-Time PCR System or 7500 Real Time PCR System (Thermo Fisher Scientific) using TaqMan Universal PCR Master Mix (Thermo Fisher Scientific) following manufacturer's instructions. RT-qPCR assays and conditions were performed as previously described (11,29,55,56). The following commercially available Assay-on-Demand gene expression products (Thermo Fisher Scientific) were used: IGF2BP1 (Hs00977566_m1), IGF2BP2 (Hs00538956_m1), IGF2BP3 (Hs01122560_g1), CA1 (Hs01100176_m1), GCNT2 (Hs00377334_m1), BCL11A (Hs00256254_m1), HMGA2 (Hs00971724_m1), ZBTB7A (Hs00792219_m1), KLF1 (Hs00610592_m1), SOX6 (Hs00264525_m1), c-MYC (Hs00153408_m1), IGF2 (Hs01005963_m1), and Beta-Actin (Hs99999903_m1).…”

Section: Methodsmentioning

confidence: 99%

IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts

Vasconcellos

Tumburu

Byrnes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Here we investigated in primary human erythroid tissues a downstream element of the heterochronic let-7 miRNA pathway, the insulinlike growth factor 2 mRNA-binding protein 1 (IGF2BP1), for its potential to affect the hemoglobin profiles in human erythroblasts. Comparison of adult bone marrow to fetal liver lysates demonstrated developmental silencing in IGF2BP1. Erythroid-specific overexpression of IGF2BP1 caused a nearly complete and pancellular reversal of the adult pattern of hemoglobin expression toward a more fetal-like phenotype. The reprogramming of hemoglobin expression was achieved at the transcriptional level by increased gamma-globin combined with decreased beta-globin transcripts resulting in gamma-globin rising to 90% of total beta-like mRNA. Delta-globin mRNA was reduced to barely detectable levels. Alpha-globin levels were not significantly changed. Fetal hemoglobin achieved levels of 68.6 ± 3.9% in the IGF2BP1 overexpression samples compared with 5.0 ± 1.8% in donor matched transduction controls. In part, these changes were mediated by reduced protein expression of the transcription factor BCL11A. mRNA stability and polysome studies suggest IGF2BP1 mediates posttranscriptional loss of BCL11A. These results suggest a mechanism for chronoregulation of fetal and adult hemoglobin expression in humans.IGF2BP1 | IMP1 | let-7 targets | fetal hemoglobin | ontogeny

show abstract

“…SOX6 has also been suggested to enhance definitive erythropoiesis in mice by stimulating erythroid cell survival, proliferation, and terminal maturation (Dumitriu et al 2006). A role for SOX6 in human globin gene regulation has not yet been examined directly, although recent work in human erythroid progenitors suggests that variation in the levels of SOX6 correlates with g-globin gene expression (Sripichai et al 2009).…”

mentioning

confidence: 99%

Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6

Xu¹,

Sankaran²,

Ni³

et al. 2010

Genes Dev.

323

346

View full text Add to dashboard Cite

The developmental switch from human fetal (g) to adult (b) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a central mediator of g-globin silencing and hemoglobin switching. Here we determine chromatin occupancy of BCL11A at the human b-globin locus and other genomic regions in vivo by high-resolution chromatin immunoprecipitation (ChIP)-chip analysis. BCL11A binds the upstream locus control region (LCR), e-globin, and the intergenic regions between g-globin and d-globin genes. A chromosome conformation capture (3C) assay shows that BCL11A reconfigures the b-globin cluster by modulating chromosomal loop formation. We also show that BCL11A and the HMG-box-containing transcription factor SOX6 interact physically and functionally during erythroid maturation. BCL11A and SOX6 co-occupy the human b-globin cluster along with GATA1, and cooperate in silencing g-globin transcription in adult human erythroid progenitors. These findings collectively demonstrate that transcriptional silencing of g-globin genes by BCL11A involves long-range interactions and cooperation with SOX6. Our findings provide insight into the mechanism of BCL11A action and new clues for the developmental gene regulatory programs that function at the b-globin locus.[Keywords: Hemoglobin switching; fetal hemoglobin; BCL11A; transcription regulation] Supplemental material is available at http://www.genesdev.org.

show abstract

Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming

Cited by 49 publications

References 43 publications

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping

IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts

Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6

Contact Info

Product

Resources

About