Yi Qiu

The American Society for Biochemistry and Molecular Biology, Orlando, Florida, United States

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Publications (21)125.78 Total impact

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    ABSTRACT: Lysine acetyltransferases (KATs) and histone deacetylases (HDACs) are important epigenetic modifiers and dynamically cycled on active gene promoters to regulate transcription. Although HDACs are recruited to gene promoters and DNA hypersensitive sites through interactions with DNA binding factors, HDAC activities are also found globally in intergenic regions where DNA binding factors are not present. It is suggested that HDACs are recruited to those regions through other distinct, yet undefined mechanisms. Here we show that HDACs can be directly recruited to chromatin in the absence of other factors through direct interactions with both DNA and core histone subunits. HDACs interact with DNA in a non-sequence specific manner. HDAC1 and p300 directly bind to the overlapping regions of the histone H3 tail and compete for histone binding. Previously we show that p300 can acetylate HDAC1 to attenuate deacetylase activity. Here we have further mapped two distinct regions of HDAC1 that interact with p300. Interestingly, these regions of HDAC1 also associate with histone H3. More importantly, p300 and HDAC1 compete for chromatin binding both in vitro and in vivo. Therefore, the mutually exclusive associations of HDAC1/p300, p300/histone, and HDAC1/histone on chromatin contribute to the dynamic regulation of histone acetylation by balancing HDAC or KAT activity present at histones to reorganize chromatin structure and regulate transcription.
    PLoS ONE 01/2014; 9(4):e94523. · 3.73 Impact Factor
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    ABSTRACT: hSETD1A is a member of the trithorax (TrxG) family of histone methyltransferases (HMTs) that methylate H3K4 at promoters of active genes. Although misregulation of MLL family proteins has been associated with acute leukemia, the role of hSETD1A in cancer remains unknown. In this study, we report that hSETD1A and its associated H3K4me3 are up-regulated in human colorectal cancer (CRC) cells and patients. Depletion of hSETD1A inhibited CRC cell growth, colony formation, and tumor engraftment. Genome-wide expression profiling of CRC cells reveals that approximately 50% of Wnt/β-catenin target genes are affected by the hSETD1A knockdown (KD) suggesting that hSETD1A regulates a subset of canonical Wnt-signaling target genes. We further demonstrate that hSETD1A is recruited to promoters of those Wnt-signaling target genes through its interaction with β-catenin, a master regulator of the Wnt-signaling pathway. The recruitment of the hSETD1A HMT complex confers promoter-associated H3K4me3 that leads to assembly of transcription preinitiation complex (PIC) and transcriptional activation. Furthermore, the expression levels of hSETD1A are positively correlated with H3K4me3 enrichment at the promoters of Wnt/β-catenin target genes and the aberrant activation of these genes in human CRC. These results provide new biologic and mechanistic insights into the cooperative role of hSETD1A and β-catenin in regulation of Wnt target genes as well as in CRC cell growth in vitro and in vivo.
    Cancer Research 11/2013; · 8.65 Impact Factor
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    ABSTRACT: Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease, yet the mechanisms that protect neurons from genotoxic stress remain largely obscure. We sought to characterize the roles of the NAD(+)-dependent deacetylase SIRT1 in the neuronal response to DNA double-strand breaks (DSBs). We found that SIRT1 was rapidly recruited to DSBs in postmitotic neurons, where it showed a synergistic relationship with ataxia telangiectasia mutated (ATM). SIRT1 recruitment to breaks was ATM dependent; however, SIRT1 also stimulated ATM autophosphorylation and activity and stabilized ATM at DSB sites. After DSB induction, SIRT1 also bound the neuroprotective class I histone deacetylase HDAC1. We found that SIRT1 deacetylated HDAC1 and stimulated its enzymatic activity, which was necessary for DSB repair through the nonhomologous end-joining pathway. HDAC1 mutations that mimic a constitutively acetylated state rendered neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promoted HDAC1 deacetylation also reduced DNA damage in two mouse models of neurodegeneration. We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration.
    Nature Neuroscience 07/2013; · 15.25 Impact Factor
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    ABSTRACT: The interplay between polycomb and trithorax complexes has been implicated in embryonic stem cell (ESC) self-renewal and differentiation. It has been shown recently that WRD5 and Dpy-30, specific components of the SET1/MLL protein complexes, play important roles during ESC self-renewal and differentiation of neural lineages. However, not much is known about how and where specific trithorax complexes are targeted to genes involved in self-renewal or lineage-specification. Here, we report that the recruitment of the hSET1A histone H3K4 methyltransferase (HMT) complex by transcription factor USF1 is required for mesoderm specification and lineage differentiation. In undifferentiated ESCs, USF1 maintains hematopoietic stem/progenitor cell (HS/PC) associated bivalent chromatin domains and differentiation potential. Furthermore, USF1 directed recruitment of the hSET1A complex to the HoxB4 promoter governs the transcriptional activation of HoxB4 gene and regulates the formation of early hematopoietic cell populations. Disruption of USF or hSET1A function by overexpression of a dominant-negative AUSF1 mutant or by RNA-interference-mediated knockdown, respectively, led to reduced expression of mesoderm markers and inhibition of lineage differentiation. We show that USF1 and hSET1A together regulate H3K4me3 modifications and transcription preinitiation complex assembly at the hematopoietic-associated HoxB4 gene during differentiation. Finally, ectopic expression of USF1 in ESCs promotes mesoderm differentiation and enforces the endothelial-to-hematopoietic transition by inducing hematopoietic-associated transcription factors, HoxB4 and TAL1. Taken together, our findings reveal that the guided-recruitment of the hSET1A histone methyltransferase complex and its H3K4 methyltransferase activity by transcription regulator USF1 safeguards hematopoietic transcription programs and enhances mesoderm/hematopoietic differentiation.
    PLoS Genetics 06/2013; 9(6):e1003524. · 8.52 Impact Factor
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    ABSTRACT: Histone deacetylases (HDACs) play important roles in regulating cell proliferation and differentiation. The HDAC1 containing NuRD complex is generally considered as a corepressor complex and is required for GATA-1 mediated repression. However, recent studies also show that the NuRD complex is involved in GATA-1 mediated gene activation. We tested whether the GATA-1 associated NuRD complex loses its deacetylase activity and commits the GATA-1 complex to become an activator during erythropoiesis. We found that GATA-1 associated deacetylase activity gradually decreased upon induction of erythroid differentiation. GATA-1 associated HDAC1 is increasingly acetylated after differentiation. It has been demonstrated earlier that acetylated HDAC1 has no deacetylase activity. Indeed, overexpression of an HDAC1 mutant, which mimics acetylated HDAC1, promotes GATA-1 mediated transcription and erythroid differentiation. Furthermore, during erythroid differentiation acetylated HDAC1 recruitment is increased at GATA-1 activated genes while significantly decreased at GATA-1 repressed genes. Interestingly, deacetylase activity is not required for Mi2 remodeling activity, suggesting that remodeling activity may be required for both activation and repression. Thus, our data suggest that NuRD can function as a coactivator or repressor and acetylated HDAC1 converts the NuRD complex from a repressor to an activator during GATA-1 directed erythroid differentiation.
    Journal of Biological Chemistry 09/2012; · 4.65 Impact Factor
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    ABSTRACT: The reversible acetylation of histones and non-histone proteins by histone acetyltransferases and deacetylases (HDACs) plays a critical role in many cellular processes in eukaryotic cells. HDAC6 is a unique histone deacetylase with two deacetylase domains and a C-terminal zinc finger domain. HDAC6 resides mainly in the cytoplasm and regulates many important biological processes, including cell migration and degradation of misfold proteins. HDAC6 has also been shown to localize in the nucleus to regulate transcription. However, how HDAC6 shuttles between the nucleus and cytoplasm is largely unknown. In addition, it is not clear how HDAC6 enzymatic activity is modulated. Here, we show that HDAC6 can be acetylated by p300 on five clusters of lysine residues. One cluster (site B) of acetylated lysine is in the N-terminal nuclear localization signal region. These lysine residues in site B were converted to glutamine to mimic acetylated lysines. The mutations significantly reduced HDAC6 tubulin deacetylase activity and further impaired cell motility, but had no effect on histone deacetylase activity. More interestingly, these mutations retained HDAC6 in the cytoplasm by blocking the interaction with the nuclear import protein importin-α. The retention of HDAC6 in the cytoplasm by acetylation eventually affects histone deacetylation. Thus, we conclude that acetylation is an important post-translational modification that regulates HDAC6 tubulin deacetylase activity and nuclear import.
    Journal of Biological Chemistry 07/2012; 287(34):29168-74. · 4.65 Impact Factor
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    03/2012; , ISBN: 978-953-51-0320-2
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    ABSTRACT: Chromatin insulators protect erythroid genes from being silenced during erythropoiesis, and the disruption of barrier insulator function in erythroid membrane gene loci results in mild or severe anemia. We showed previously that the USF1/2-bound 5'HS4 insulator mediates chromatin barrier activity in the erythroid-specific chicken β-globin locus. It is currently not known how insulators establish such a barrier. To understand the function of USF1, we purified USF1-associated protein complexes and found that USF1 forms a multiprotein complex with hSET1 and NURF, thus exhibiting histone H3K4 methyltransferase- and ATP-dependent nucleosome remodeling activities, respectively. Both SET1 and NURF are recruited to the 5'HS4 insulator by USF1 to retain the active chromatin structure in erythrocytes. Knock-down of NURF resulted in a rapid loss of barrier activity accompanied by an alteration of nucleosome positioning, increased occupancy of the nucleosome-free linker region at the insulator site, and increased repressive H3K27me3 levels in the vicinity of the HS4 insulator. Furthermore, suppression of SET1 reduced barrier activity, decreased H3K4me2 and acH3K9/K14, and diminished the recruitment of BPTF at several erythroid-specific barrier insulator sites. Therefore, our data reveal a synergistic role of hSET1 and NURF in regulating the USF-bound barrier insulator to prevent erythroid genes from encroachment of heterochromatin.
    Blood 06/2011; 118(5):1386-94. · 9.06 Impact Factor
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    ABSTRACT: Although histone deacetylases (HDACs) are normally considered as co-repressors, HDAC1 has been identified as a coactivator for the glucocorticoid receptor (GR) (Qiu, Y., Zhao, Y., Becker, M., John, S., Parekh, B. S., Huang, S., Hendarwanto, A., Martinez, E. D., Chen, Y., Lu, H., Adkins, N. L., Stavreva, D. A., Wiench, M., Georgel, P. T., Schiltz, R. L., and Hager, G. L. (2006) Mol. Cell 22, 669-679). Furthermore, HDAC1 is acetylated, and its acetylation level is linked to the transcription state of a GR-induced promoter (mouse mammary tumor virus). GR is also known to interact dynamically with regulatory elements in living cells (McNally, J. G., Müller, W. G., Walker, D., Wolford, R., and Hager, G. L. (2000) Science 287, 1262-1265). However, HDAC1 dynamics have never been studied. We demonstrate here that HDAC1 also exchanges rapidly with promoter chromatin, and its exchange rate is significantly modulated during the development of promoter activity. Prior to induction, HDAC1 mobility was retarded compared with the exchange rate for GR. HDAC1 mobility then increased substantially, coordinately with the peak of promoter activity. At later time points, promoter activity was severely repressed, and HDAC1 mobility returned to the rate of exchange observed for the uninduced promoter. Thus, alterations of the exchange rates of HDAC1 at the promoter are correlated with the activity state of the promoter. These findings provide direct evidence for the functional role of highly mobile transcription factor complexes in transcription regulation.
    Journal of Biological Chemistry 12/2010; 286(9):7641-7. · 4.65 Impact Factor
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    ABSTRACT: HDAC1 and -2 are highly conserved enzymes and often coexist in the same coregulator complexes. Understanding the regulation of histone deacetylase activities is extremely important because these enzymes play key roles in epigenetic regulation in normal and cancer cells. We previously showed that HDAC1 is required for glucocorticoid receptor-mediated transcription activation and that its activity is regulated through acetylation by p300 during the induction cycle. Here, we showed that HDAC2 is also required for glucocorticoid receptor-mediated gene activation. HDAC2, however, is regulated through a different mechanism from that of HDAC1. HDAC2 is not acetylated by p300, although 5 of 6 acetylated lysine residues in HDAC1 are also present in HDAC2. More importantly, the activity of HDAC2 is inhibited by acetylated HDAC1. Additionally, we showed that acetylated HDAC1 can trans-regulate HDAC2 through heterodimerization. Thus, this study uncovered fundamental differences between HDAC1 and HDAC2. It also unveiled a new mechanism of collaborative regulation by HDAC1/2 containing coregulator complexes.
    Journal of Biological Chemistry 10/2009; 284(50):34901-10. · 4.65 Impact Factor
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    ABSTRACT: TAL1/SCL (hereafter referred to as TAL1) is a critical transcription factor required for hematopoiesis in which hematopoietic stem cells commit and differentiate to different lineages. During this process, transcription of many genes is turned on and off in part by epigenetic mechanisms. TAL1 has recently been shown to differentially recruit LSD1 and other histone modifying complexes to regulate its target genes. Here, we focus primarily on epigenetic mechanisms that are regulated by TAL1 during normal and malignant hematopoiesis. We discuss how different histone modifying enzymes are recruited by TAL1 and how these enzymatic activities mediate the activating or repressive function of TAL1. Finally, we further explore the possible mechanisms by which dysregulation of the recruitment and activity of histone modifying enzymes contribute to leukemogenesis.
    Epigenetics: official journal of the DNA Methylation Society 09/2009; 4(6):357-61. · 4.58 Impact Factor
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    ABSTRACT: TAL1 is a critical transcription factor required for hematopoiesis. However, perturbation of its activity often leads to T cell leukemia. Whether and how its transcriptional activities are regulated during hematopoiesis remains to be addressed. Here, we show that TAL1 is associated with histone demethylase complexes containing lysine-specific demethylase 1 (LSD1), RE1 silencing transcription factor corepressor (CoREST), histone deacetylase 1 (HDAC1), and histone deacetylase 2 in erythroleukemia and T cell leukemia cells. The enzymatic domain of LSD1 plays an important role in repressing the TAL1-directed transcription of GAL4 reporter linked to a thymidine kniase minimal promoter. Furthermore, we demonstrate that the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated during the early phases of erythroid differentiation. Consistent with the rapid changes of TAL1-corepressor complex during differentiation, TAL1 recruits LSD1 to the silenced p4.2 promoter in undifferentiated, but not in differentiated, murine erythroleukemia (MEL) cells. Finally, shRNA-mediated knockdown of LSD1 in MEL cells resulted in derepression of the TAL1 target gene accompanied by increasing dimeH3K4 at the promoter region. Thus, our data revealed that histone lysine demethylase LSD1 may negatively regulate TAL1-mediated transcription and suggest that the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs.
    Proceedings of the National Academy of Sciences 07/2009; 106(25):10141-6. · 9.74 Impact Factor
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    ABSTRACT: PRMTs (protein arginine N-methyltransferases) specifically modify the arginine residues of key cellular and nuclear proteins as well as histone substrates. Like lysine methylation, transcriptional repression or activation is dependent upon the site and type of arginine methylation on histone tails. Recent discoveries imply that histone arginine methylation is an important modulator of dynamic chromatin regulation and transcriptional controls. However, under the shadow of lysine methylation, the roles of histone arginine methylation have been under-explored. The present review focuses on the roles of histone arginine methylation in the regulation of gene expression, and the interplays between histone arginine methylation, histone acetylation, lysine methylation and chromatin remodelling factors. In addition, we discuss the dynamic regulation of arginine methylation by arginine demethylases, and how dysregulation of PRMTs and their activities are linked to human diseases such as cancer.
    Bioscience Reports 05/2009; 29(2):131-41. · 1.88 Impact Factor
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    ABSTRACT: The insulator element at the 5' end of the chicken beta-globin locus acts as a barrier, protecting transgenes against silencing effects of adjacent heterochromatin. We showed earlier that the transcription factor USF1 binds within the insulator and that this site is important for generating in adjacent nucleosomes histone modifications associated with active chromatin and, by inference, with barrier function. To understand the mechanism of USF1 action, we have characterized USF1-containing complexes. USF1 interacts directly with the histone H4R3-specific methyltransferase PRMT1. USF1, PRMT1, and the histone acetyltransferases (HATs) PCAF and SRC-1 form a complex with both H4R3 histone methyltransferase and HAT activities. Small interfering RNA downregulation of USF1 results in localized loss of H4R3 methylation, and other histone modifications associated with euchromatin, at the insulator. A dominant negative peptide that interferes with USF1 binding to DNA causes silencing of an insulated reporter construct, indicating abolition of barrier function. These results show that USF1 plays a direct role in maintaining the barrier, supporting a model in which the insulator works as a barrier by maintaining a local environment of active chromatin.
    Molecular and cellular biology 12/2007; 27(22):7991-8002. · 6.06 Impact Factor
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    EMBO Reports 12/2007; 8(11):977-81. · 7.19 Impact Factor
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    ABSTRACT: omen constitute approximately 45% of the postdoctoral fellows in the biomedical sciences at universities and research institutions in the uSa, but a much lower percent - age of women hold faculty positions. in the uS national institutes of Health (niH; Bethesda, MD) intramural research program, for example, women make up only 29% of the tenure-track investiga - tors and hold just 19% of the tenured sen - ior investigator appointments. a similar disparity between the ratio of men and women in independent faculty positions exists in most academic institutions across the uSa (nelson, 2005; nSF, 2004, 2006), and statistics from Europe show a similar trend of women disappearing from the higher echelons of academia (E c, 2006). the transition from postdoctoral fellow to faculty is a period during which a wor - rying number of women leave academic research. Several recent surveys have tried to identify factors that lead to the attrition of women from the life sciences and engi -
    Embo Reports - EMBO REP. 01/2007; 8(11):977-981.
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    ABSTRACT: Although histone deacetylases (HDACs) are generally viewed as corepressors, we show that HDAC1 serves as a coactivator for the glucocorticoid receptor (GR). Furthermore, a subfraction of cellular HDAC1 is acetylated after association with the GR, and this acetylation event correlates with a decrease in promoter activity. HDAC1 in repressed chromatin is highly acetylated, while the deacetylase found on transcriptionally active chromatin manifests a low level of acetylation. Acetylation of purified HDAC1 inactivates its deacetylase activity, and mutation of the critical acetylation sites abrogates HDAC1 function in vivo. We propose that hormone activation of the receptor leads to progressive acetylation of HDAC1 in vivo, which in turn inhibits the deacetylase activity of the enzyme and prevents a deacetylation event that is required for promoter activation. These findings indicate that HDAC1 is required for the induction of some genes by the GR, and this activator function is dynamically modulated by acetylation.
    Molecular Cell 07/2006; 22(5):669-79. · 15.28 Impact Factor
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    ABSTRACT: Eucaryotic gene transcriptional switches utilize changes both in the activity and composition of soluble transcription factor complexes, and epigenetic modifications to the chromatin template. Until recently, alternate states of promoter activity have been associated with the assembly of relatively stable multiprotein complexes on target genes, with transitions in the composition of these complexes occurring on the time scale of minutes or hours. The development of living cell techniques to characterize transcription factor function in real time has led to an alternate view of highly dynamic protein/template interactions. In addition, emerging evidence suggests that energy-dependent processes contribute significantly to the rapid movement of proteins in living cells, and to the exchange of sequence-specific DNA-binding proteins with regulatory elements. Potential mechanisms involved in the unexpectedly rapid flux of factor/template interactions are discussed in the context of a "return-to-template" model for transcription factor function.
    Chromosome Research 02/2006; 14(1):107-16. · 2.85 Impact Factor
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    ABSTRACT: Through the use of novel imaging techniques, we have observed direct steroid receptor binding to a tandem array of a hormone-responsive promoter in living cells. We found that the glucocorticoid receptor (GR) exchanges rapidly with regulatory elements in the continued presence of ligand. We have also reconstituted a GR-dependent nucleoprotein transition with chromatin assembled on promoter DNA, and we discovered that GR is actively displaced from the chromatin template during the chromatin remodeling process. Using high-intensity UV laser crosslinking, we have observed highly periodic interactions of GR with promoter chromatin. These periodic binding events are dependent on GR-directed hSWI/SNF remodeling of the template and require the presence of ATP. Both the in vitro and in vivo results are consistent with a dynamic model (“hit-and-run”) in which GR first binds to chromatin after ligand activation, recruits a remodeling activity, and is simultaneously lost from the template. We also find that receptor mobility in the nucleoplasm is strongly enhanced by molecular chaperones. These observations indicate that multiple mechanisms are involved in transient receptor interactions with nucleoplasmic targets.
    Annals of the New York Academy of Sciences 01/2006; 1024(1):213 - 220. · 4.38 Impact Factor
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    ABSTRACT: The BETA2 transcription factor influences islet beta cell development and function. Activation of insulin gene transcription by this member of the basic helix-loop-helix gene family is mediated by p300 through the ability of this coactivator to form a functional bridge between the basal transcriptional apparatus, BETA2, and PDX-1, another key transcription factor. In this report, we examined whether BETA2-mediated stimulation was also directly influenced by the acetyltransferase activities of p300 or the p300-associated factor. BETA2 was specifically and selectively acetylated by p300-associated factor in beta cells. Sites of BETA2 acetylation were found within the loop region of the basic helix-loop-helix DNA binding/dimerization domain and a more C-terminal region involved in activation. Insulin gene transcription was decreased by blocking acetylation of BETA2 because of effects on DNA binding and activation potential. These findings suggest that acetylation of BETA2 plays a role in controlling the activation state of this islet regulatory factor.
    Journal of Biological Chemistry 04/2004; 279(11):9796-802. · 4.65 Impact Factor

Publication Stats

432 Citations
125.78 Total Impact Points


  • 2013
    • The American Society for Biochemistry and Molecular Biology
      Orlando, Florida, United States
  • 2009–2012
    • University of Florida
      • Department of Anatomy and Cell Biology
      Gainesville, FL, United States
    • Ball State University
      • Center for Medical Education
      Muncie, Indiana, United States
    • Jilin University
      • College of Life Sciences
      Changchun, Jilin Sheng, China
  • 2006
    • National Institutes of Health
      • Laboratory of Receptor Biology and Gene Expression
      Bethesda, MD, United States
    • National Cancer Institute (USA)
      • Laboratory of Receptor Biology and Gene Expression
      Maryland, United States
  • 2002–2004
    • Vanderbilt University
      • Department of Molecular Physiology and Biophysics
      Nashville, MI, United States