Lihong Shi

Publications (6)53 Total impact

• Article: Disruption of the Hbsl1-Myb Locus Causes Hereditary Persistence of Fetal Hemoglobin in Mouse.

  Mikiko Suzuki, Hiromi Yamazaki, Harumi Y Mukai, Hozumi Motohashi, Lihong Shi, Osamu Tanabe, James Douglas Engel, Masayuki Yamamoto
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  ABSTRACT: The human β-globin locus is comprised of embryonic, fetal and adult globin genes, each of which is expressed at distinct stages of pre- and post-natal development. Functional defects in globin proteins or expression results in mild to severe anemia, such as in sickle-cell disease or β-thalassemia, but the clinical symptoms of both disorders are ameliorated by persistent expression of the fetal globin genes. Recent genome wide association studies (GWAS) identified the intergenic region between the HBS1L and MYB loci as a candidate modifier of fetal hemoglobin expression in adults. However, it remains to be clarified whether the enhancer activity within the HBS1L-MYB regulatory domain contributes to the production of fetal hemoglobin in adults. Here we report a new mouse model of hereditary persistence of fetal hemoglobin (HPFH) in which a transgene randomly inserted into the orthologous murine Hbs1l-Myb locus. This mutant mouse exhibited typically elevated expression of embryonic globins and hematopoietic parameters similar to those observed in human HPFH. These results support the contention that mutation of the HBS1L-MYB genomic domain is responsible for elevated expression of the fetal globin genes, and this model serves as an important means in the analysis of networks that regulate fetal globin gene expression.
  Molecular and cellular biology 02/2013; · 6.06 Impact Factor
• Article: Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction.

  Lihong Shi, Shuaiying Cui, James D Engel, Osamu Tanabe
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  ABSTRACT: Enhanced fetal γ-globin synthesis alleviates symptoms of β-globinopathies such as sickle cell disease and β-thalassemia, but current γ-globin-inducing drugs offer limited beneficial effects. We show here that lysine-specific demethylase 1 (LSD1) inhibition by RNAi in human erythroid cells or by the monoamine oxidase inhibitor tranylcypromine in human erythroid cells or β-type globin-transgenic mice enhances γ-globin expression. LSD1 is thus a promising therapeutic target for γ-globin induction, and tranylcypromine may serve as a lead compound for the development of a new γ-globin inducer.
  Nature medicine 02/2013; 19(3):291-4. · 27.14 Impact Factor
• Article: Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes.

  Andrew D Campbell, Shuaiying Cui, Lihong Shi, Rebekah Urbonya, Andrea Mathias, Kori Bradley, Kwaku O Bonsu, Rhonda R Douglas, Brittne Halford, Lindsay Schmidt, David Harro, Donald Giacherio, Keiji Tanimoto, Osamu Tanabe, James Douglas Engel
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  ABSTRACT: Sickle cell disease (SCD) is a hematologic disorder caused by a missense mutation in the adult β-globin gene. Higher fetal hemoglobin (HbF) levels in red blood cells of SCD patients have been shown to improve morbidity and mortality. We previously found that nuclear receptors TR2 and TR4 repress expression of the human embryonic ε-globin and fetal γ-globin genes in definitive erythroid cells. Because forced expression of TR2/TR4 in murine adult erythroid cells paradoxically enhanced fetal γ-globin gene expression in transgenic mice, we wished to determine if forced TR2/TR4 expression in a SCD model mouse would result in elevated HbF synthesis and thereby alleviate the disease phenotype. In a "humanized" sickle cell model mouse, forced TR2/TR4 expression increased HbF abundance from 7.6% of total hemoglobin to 18.6%, accompanied by increased hematocrit from 23% to 34% and reticulocyte reduction from 61% to 18%, indicating a significant reduction in hemolysis. Moreover, forced TR2/TR4 expression reduced hepatosplenomegaly and liver parenchymal necrosis and inflammation in SCD mice, indicating alleviation of usual pathophysiological characteristics. This article shows that genetic manipulation of nonglobin proteins, or transcription factors regulating globin gene expression, can ameliorate the disease phenotype in a SCD model animal. This proof-of-concept study demonstrates that modulating TR2/TR4 activity in SCD patients may be a promising therapeutic approach to induce persistent HbF accumulation and for treatment of the disease.
  Proceedings of the National Academy of Sciences 11/2011; 108(46):18808-13. · 9.68 Impact Factor
• Article: Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic β-type globin promoters in differentiated adult erythroid cells.

  Shuaiying Cui, Katarzyna E Kolodziej, Naoshi Obara, Alexandra Amaral-Psarris, Jeroen Demmers, Lihong Shi, James Douglas Engel, Frank Grosveld, John Strouboulis, Osamu Tanabe
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  ABSTRACT: Nuclear receptors TR2 and TR4 (TR2/TR4) were previously shown to bind in vitro to direct repeat elements in the mouse and human embryonic and fetal β-type globin gene promoters and to play critical roles in the silencing of these genes. By chromatin immunoprecipitation (ChIP) we show that, in adult erythroid cells, TR2/TR4 bind to the embryonic β-type globin promoters but not to the adult β-globin promoter. We purified protein complexes containing biotin-tagged TR2/TR4 from adult erythroid cells and identified DNMT1, NuRD, and LSD1/CoREST repressor complexes, as well as HDAC3 and TIF1β, all known to confer epigenetic gene silencing, as potential corepressors of TR2/TR4. Coimmunoprecipitation assays of endogenous abundance proteins indicated that TR2/TR4 complexes consist of at least four distinct molecular species. In ChIP assays we found that, in undifferentiated murine adult erythroid cells, many of these corepressors associate with both the embryonic and the adult β-type globin promoters but, upon terminal differentiation, they specifically dissociate only from the adult β-globin promoter concomitant with its activation but remain bound to the silenced embryonic globin gene promoters. These data suggest that TR2/TR4 recruit an array of transcriptional corepressors to elicit adult stage-specific silencing of the embryonic β-type globin genes through coordinated epigenetic chromatin modifications.
  Molecular and cellular biology 06/2011; 31(16):3298-311. · 6.06 Impact Factor
• Source

  Available from: Maureen A Sartor

  Article: Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes.

  Henriette O'Geen, Yu-Hsuan Lin, Xiaoqin Xu, Lorigail Echipare, Vitalina M Komashko, Daniel He, Seth Frietze, Osamu Tanabe, Lihong Shi, Maureen A Sartor, James D Engel, Peggy J Farnham
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  ABSTRACT: The orphan nuclear receptor TR4 (human testicular receptor 4 or NR2C2) plays a pivotal role in a variety of biological and metabolic processes. With no known ligand and few known target genes, the mode of TR4 function was unclear. We report the first genome-wide identification and characterization of TR4 in vivo binding. Using chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq), we identified TR4 binding sites in 4 different human cell types and found that the majority of target genes were shared among different cells. TR4 target genes are involved in fundamental biological processes such as RNA metabolism and protein translation. In addition, we found that a subset of TR4 target genes exerts cell-type specific functions. Analysis of the TR4 binding sites revealed that less than 30% of the peaks from any of the cell types contained the DR1 motif previously derived from in vitro studies, suggesting that TR4 may be recruited to the genome via interaction with other proteins. A bioinformatics analysis of the TR4 binding sites predicted a cis regulatory module involving TR4 and ETS transcription factors. To test this prediction, we performed ChIP-seq for the ETS factor ELK4 and found that 30% of TR4 binding sites were also bound by ELK4. Motif analysis of the sites bound by both factors revealed a lack of the DR1 element, suggesting that TR4 binding at a subset of sites is facilitated through the ETS transcription factor ELK4. Further studies will be required to investigate the functional interdependence of these two factors. Our data suggest that TR4 plays a pivotal role in fundamental biological processes across different cell types. In addition, the identification of cell type specific TR4 binding sites enables future studies of the pathways underlying TR4 action and its possible role in metabolic diseases.
  BMC Genomics 01/2010; 11:689. · 4.07 Impact Factor
• Article: Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic $beta$-type globin promoters in differentiated adult erythroid cells.

  Shuaiying Cui, Katarzyna E Kolodziej, Naoshi Obara, Alexandra Amaral-Psarris, Jeroen Demmers, Lihong Shi, James Douglas Engel, Frank Grosveld, John Strouboulis, Osamu Tanabe
  [show abstract] [hide abstract]
  ABSTRACT: Nuclear receptors TR2 and TR4 (TR2/TR4) were previously shown to bind in vitro to direct repeat elements in the mouse and human embryonic and fetal $beta$-type globin gene promoters and to play critical roles in the silencing of these genes. By chromatin immunoprecipitation (ChIP) we show that, in adult erythroid cells, TR2/TR4 bind to the embryonic $beta$-type globin promoters but not to the adult $beta$-globin promoter. We purified protein complexes containing biotin-tagged TR2/TR4 from adult erythroid cells and identified DNMT1, NuRD, and LSD1/CoREST repressor complexes, as well as HDAC3 and TIF1$beta$, all known to confer epigenetic gene silencing, as potential corepressors of TR2/TR4. Coimmunoprecipitation assays of endogenous abundance proteins indicated that TR2/TR4 complexes consist of at least four distinct molecular species. In ChIP assays we found that, in undifferentiated murine adult erythroid cells, many of these corepressors associate with both the embryonic and the adult $beta$-type globin promoters but, upon terminal differentiation, they specifically dissociate only from the adult $beta$-globin promoter concomitant with its activation but remain bound to the silenced embryonic globin gene promoters. These data suggest that TR2/TR4 recruit an array of transcriptional corepressors to elicit adult stage-specific silencing of the embryonic $beta$-type globin genes through coordinated epigenetic chromatin modifications.
  Molecular and cellular biology. 31(16):3298-311.