Structural Basis for CoREST-Dependent Demethylation of Nucleosomes by the Human LSD1 Histone Demethylase

Yang, Maojun; Gocke, Christian B.; Luo, Xuelian; Borek, Dominika; Tomchick, Diana R.; Machius, Mischa; Otwinowski, Zbyszek; Yu, Hongtao

doi:10.1016/j.molcel.2006.07.012

Cited by 294 publications

(397 citation statements)

References 47 publications

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“…LSD1 associated CoREST and NURD complexes also contain class I HDAC-associated HDAC activity (9,10,19,32). Consistent with this, and with our previously reported findings that treatment with pan-HDI PS induces differentiation in AML blast progenitor cells (22), our present in vitro findings confirm that co-treatment with SP2509 or knockdown of LSD1 by shRNA enhanced the lethal effects of relatively low and clinically achievable concentrations of PS in AML cells (30,31).…”

Section: Sp2509 Is a Small Molecule Reversible Inhibitor Of Lsd1 (19)supporting

confidence: 91%

“…Unlike the situation in the cell-free enzyme assay, the lower intracellular potency of SP2509 is likely due to the presence and activity of LSD1 in the regulatory protein complexes in the intracellular setting, and the potential regulation of the biologic outcome of LSD1 inhibition by other intracellular factors (9,10,19). For example, the demethylase activity of LSD1 at the nucleosomes is enhanced by its association with the co-repressor complexes such as Co-REST and NURD (9,19,32). Our studies also show that the binding of LSD1 and CoREST is partially disrupted by SP2509 treatment.…”

Section: Sp2509 Is a Small Molecule Reversible Inhibitor Of Lsd1 (19)supporting

confidence: 54%

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Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

Fiskus¹,

Sharma²,

Shah³

et al. 2017

Leukemia

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The histone demethylase LSD1 (KDM1A) demethylates mono-and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in AML. Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the co-repressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and C/EBPα in cultured AML cells. Additionally, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphologic features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than MLL fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Cotreatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared to each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML. KeywordsKDM1A; histone deacetylase inhibitor; acute myeloid leukemia; differentiation Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

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Section: Sp2509 Is a Small Molecule Reversible Inhibitor Of Lsd1 (19)supporting

confidence: 91%

Section: Sp2509 Is a Small Molecule Reversible Inhibitor Of Lsd1 (19)supporting

confidence: 54%

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

Fiskus¹,

Sharma²,

Shah³

et al. 2017

Leukemia

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“…Another intriguing aspect of LSD1 function has been revealed by studying GH gene repression in lactotropes, which arise largely postnatally and independently of somatotropes [46,53 ]. In postnatal lactotropes, a signal-induced expression of ZEB1, as well as two other components of the CtBP-CoREST-LSD1 corepressor complex LCoR, PC2, tethers LSD1-containing corepressor complex to the GH promoter via a ZEB1 recognition site and represses GH gene expression apparently in LSD1 dependent fashion, suggesting that the function of LSD1 in transcriptional regulation is cell-type specific and is modulated by its associated partners, consistent with previous findings that CoREST, a SANT domain containing protein, and BHC80, a PHD domain containing protein, can regulate LSD1 activity [54][55][56].…”

Section: Lsd1 Developmentally Regulates Both Gene Activation and Reprsupporting

confidence: 89%

Signaling and epigenetic regulation of pituitary development

Zhu

Wang

et al. 2007

Current Opinion in Cell Biology

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The developing pituitary gland provides an instructive model system for elucidating the molecular mechanisms by which distinct cell types arise from a common progenitor lineage accompanied by changes in the chromatin status in response to multiple extrinsic and intrinsic signals. Recent studies have shed light on the integration between signaling molecules and activation of transcription factors that are essential for cell fate commitment and terminal differentiation. Investigation of the in vivo function of the histone modifying enzyme LSD1 has revealed a new layer of regulatory mechanism in pituitary organogenesis. Epigenetic studies of the transcriptional events in terminal differentiation process have provided insights into the functions of non-coding RNA and developmentally regulated chromatin organization.

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“…Interactions of several LSD1-CoREST subunits with some transcription factors (11,(24)(25)(26) or with long noncoding RNAs (27) The SANT2 domain of CoREST is required for the efficient demethylation of nucleosomes by the LSD1-CoREST dimer and seems to be essential for a correct presentation of the substrate to the LSD1 catalytic site (29). The role of the HMG domain of Braf35 is less clear.…”

Section: Discussionmentioning

confidence: 99%

Control of neuronal differentiation by sumoylation of BRAF35, a subunit of the LSD1-CoREST histone demethylase complex

Ceballos-Chávez

Rivero

García-Gutiérrez³

et al. 2012

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

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The LSD1-CoREST histone demethylase complex is required to repress neuronal genes in nonneuronal tissues. Here we show that sumoylation of Braf35, one of the subunits of the complex, is required to maintain full repression of neuron-specific genes and for occupancy of the LSD1-CoREST complex at its gene targets. Interestingly, expression of Braf35 was sufficient to prevent neuronal differentiation induced by bHLH neurogenic transcription factors in P19 cells and in neuronal progenitors of the chicken embryo neural tube. Sumoylation of Braf35 is required for this antineurogenic activity. We also show that iBraf, a paralogue of Braf35, forms heterodimers with Braf35. Braf35-iBraf heterodimerization impairs Braf35 interaction with the LSD1-CoREST complex and inhibits Braf35 sumoylation. Consistent with these results, iBraf prevents the antineurogenic activity of Braf35 in vivo. Our data uncover a mechanism of regulation of the LSD1-CoREST complex and provide a molecular explanation for the antagonism between Braf35 and iBraf in neuronal differentiation.C ell differentiation involves large modifications of gene expression that require extensive changes of chromatin epigenetic marks (1). Epigenetic marks are DNA or histone posttranslational modifications that are inherited through cell division and that inform about the transcriptional state of loci. Among histone modifications, histone lysine methylation is of particular interest in development for the broad range of processes in which it is involved, including maintenance of stem cell pluripotency, germ-line determination, cell differentiation, control of HOX genes expression, and so forth (2, 3). Histone lysine methylation was considered a stable posttranslational modification until the discovery of histone demethylases. LSD1/KDM1 (lysine-specific demethylase 1) was the first demethylase identified and catalyzes demethylation of both di-and monomethylated lysine 4 (K4) or lysine 9 (K9) of histone H3 (H3K4me2/1 or H3K9me2/1) (4, 5). The lysine specificity of LSD1 seems to depend on its molecular partners. Thus, when LSD1 is associated with CoREST in the LSD1-CoREST corepressor complex (also called BHC, BRAF-histone deacetylase complex), the preferred substrate is H3K4me2/1, consistent with the fact that methylation of H3K4 is a mark of transcriptionaly active genes. In addition to LSD1 and CoREST, the LSD1-CoREST complex also contains HDAC1-2, BHC80, and BRAF35 (also called HMG20B) (6-9). BRAF35 contains a high-mobility group (HMG) domain and a coiled-coil domain, but its function within the complex is not well-understood (7, 10). Several functions of the LSD1-CoREST complex in differentiation and development have been reported (2). One of the best-characterized functions of the complex is its role in repression of neuronal genes in nonneuronal tissues and neuronal progenitors through its interaction with repressor factor REST (RE1 silencing transcription factor) (11,12). iBRAF (inhibitor of BRAF35, also called HMG20A) is a close paralogue of BRAF35 (13). As BRAF35...

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Structural Basis for CoREST-Dependent Demethylation of Nucleosomes by the Human LSD1 Histone Demethylase

Cited by 294 publications

References 47 publications

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

Signaling and epigenetic regulation of pituitary development

Control of neuronal differentiation by sumoylation of BRAF35, a subunit of the LSD1-CoREST histone demethylase complex

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