Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

Bradner, James E.; Mak, Raymond H.; Tanguturi, Shyam; Mazitschek, Ralph; Haggarty, Stephen J.; Ross, Kenneth N.; Chang, Cindy Y.; Bosco, J.; West, Nathan; Morse, Elizabeth M.; Lin, Katherine I.; Shen, John Paul; Kwiatkowski, Nicholas; Gheldof, Nele; Dekker, Job; DeAngelo, Daniel J.; Carr, Steven A.; Schreiber, Stuart L.; Golub, Todd R.; Ebert, Benjamin L.

doi:10.1073/pnas.1006774107

Cited by 183 publications

(189 citation statements)

References 33 publications

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“…2B). HDAC1 and HDAC2 have also been identified as HbF inducers by a chemical genetic screen (25). These results collectively provide strong support for important roles of several enzymatic subunits within the NuRD complex in globin expression, yet the extent to which various effects can be ascribed directly to action in concert with BCL11A or independently are difficult to discern.…”

Section: Discussionmentioning

confidence: 88%

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Bauer

Kerényi

et al. 2013

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

197

188

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Reactivation of fetal hemoglobin (HbF) in adults ameliorates the severity of the common β-globin disorders. The transcription factor BCL11A is a critical modulator of hemoglobin switching and HbF silencing, yet the molecular mechanism through which BCL11A coordinates the developmental switch is incompletely understood. Particularly, the identities of BCL11A cooperating protein complexes and their roles in HbF expression and erythroid development remain largely unknown. Here we determine the interacting partner proteins of BCL11A in erythroid cells by a proteomic screen. BCL11A is found within multiprotein complexes consisting of erythroid transcription factors, transcriptional corepressors, and chromatinmodifying enzymes. We show that the lysine-specific demethylase 1 and repressor element-1 silencing transcription factor corepressor 1 (LSD1/CoREST) histone demethylase complex interacts with BCL11A and is required for full developmental silencing of mouse embryonic β-like globin genes and human γ-globin genes in adult erythroid cells in vivo. In addition, LSD1 is essential for normal erythroid development. Furthermore, the DNA methyltransferase 1 (DNMT1) is identified as a BCL11A-associated protein in the proteomic screen. DNMT1 is required to maintain HbF silencing in primary human adult erythroid cells. DNMT1 haploinsufficiency combined with BCL11A deficiency further enhances γ-globin expression in adult animals. Our findings provide important insights into the mechanistic roles of BCL11A in HbF silencing and clues for therapeutic targeting of BCL11A in β-hemoglobinopathies.gene regulation | globin switching | hematopoiesis

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Section: Discussionmentioning

confidence: 88%

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Bauer

Kerényi

et al. 2013

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

197

188

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“…When BCL11A is absent, the conformation of the b-globin locus changes such that the upstream enhancer known as the locus control region is juxtaposed with the transcriptionally activated g-globin genes. A similar phenomenon occurs when cells are treated with HDAC inhibitors that induce g-globin gene expression (Bradner et al 2010). However, it is unclear if these conformational alterations are directly mediated by BCL11A or if these alterations occur secondarily to the HbF-inductive effect of BCL11A (or HDAC) inhibition.…”

Section: The Promise Of Improved Therapies Through Molecular Studies mentioning

confidence: 93%

“…A variety of HDAC inhibitors are potent inducers of HbF in vitro and further work is needed to study these molecules (Cao et al 2004;Atweh and Fathallah 2010;Bradner et al 2010). Although the majority of studies have been focused on nonspecific HDAC inhibitors, recent work suggests that inhibitors of specific HDACs, such as HDAC 1 and 2, may allow improved efficacy of HbF induction while potentially minimizing toxicity (Bradner et al 2010). …”

Section: Early Molecular Studies Lead To Therapeutic Approaches For Hmentioning

confidence: 99%

“…It was additionally shown that BCL11A directly interacts with chromatin at the human b-globin locus in primary erythroid cells and that it appeared to act as part of a complex with the transcription factor GATA1 and the NuRD chromatin remodeling and repressor complex . Of interest, the NuRD complex contains HDACs 1 and 2, which have been suggested to be the critical HDACs necessary for HbF silencing (Bradner et al 2010). In addition, it has been suggested that the transcription factor SOX6 may cooperate with BCL11A to help silence the g-globin genes in humans and it may be essential for binding the proximal promoter of these globin genes .…”

Section: The Promise Of Improved Therapies Through Molecular Studies mentioning

confidence: 99%

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The Switch from Fetal to Adult Hemoglobin

Sankaran

Orkin

2012

Cold Spring Harbor Perspectives in Medicine

249

178

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The fetal-to-adult hemoglobin switch and silencing of fetal hemoglobin (HbF) have been areas of long-standing interest among hematologists, given the fact that clinical induction of HbF production holds tremendous promise to ameliorate the clinical symptoms of sickle cell disease (SCD) and b-thalassemia. In this article, we discuss historic attempts to induce HbF that have resulted in some therapeutic approaches to manage SCD and b-thalassemia. We then go on to discuss how more recent molecular studies that have identified regulators, including BCL11A, MYB, and KLF1, hold great promise to develop targeted and more effective approaches for HbF induction. We go on to discuss strategies by which such approaches may be developed. Older studies in this field can provide important lessons for future studies aimed at developing more effective strategies for HbF induction, and we therefore chronologically cover the work accomplished as this field has evolved over the course of the past four decades.A s with many facets of the history of the hemoglobin field, the study of the fetal-toadult hemoglobin switch and work on fetal hemoglobin silencing has a rich and storied history that spans the course of several decades. In this work, we begin with a historic overview of this field and then move on to discuss more recent molecular findings that are providing important new insight into this process. There is great hope that these new molecular studies may lead to important targeted therapeutic advances for fetal hemoglobin (HbF) induction. However, the historic work in this field suggests that the road to effective therapies may not always be straightforward and reconsidering seemingly simple observations can often yield important new insights. There are many valuable lessons that can be learned from both the historic and more recent work in this field and therefore we attempt to cover the chronology of findings that have resulted in our current understanding of the fetal-to-adult hemoglobin switch.The disorders of b-hemoglobin, sickle cell disease (SCD) and b-thalassemia, are major sources of morbidity and mortality worldwide (Weatherall et al. 2006). These diseases are the

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“…15 "A further breakthrough for the new generation of selective HDAC inhibitors will be in moving them into nononcology domains in the clinic, " Jones told SciBX. In 2010, researchers at the Broad Institute and Harvard Medical School published data from a chemical genetics screen suggesting that combined inhibition of HDAC1 and HDAC2 could help stimulate the production of fetal hemoglobin, 16 which could be useful for treating sickle cell disease and b-thalassemia.…”

Section: Attention To the Oldmentioning

confidence: 99%

Clinical takeoff for new epigenetic targets

Lou¹

2013

Science-Business eXchange

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Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

Cited by 183 publications

References 33 publications

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

The Switch from Fetal to Adult Hemoglobin

Clinical takeoff for new epigenetic targets

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