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Cantor, Alan

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Cantor

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Alan

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Cantor, Alan

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2010 - 20207

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Author's Publications: search.filters.isAuthorOfPublication.4bde04ea-1910-4515-803b-3a9345cef915

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Now showing 1 - 7 of 7
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    Direct Recruitment of Polycomb Repressive Complex 1 to Chromatin by Core Binding Transcription Factors
    (Elsevier BV, 2012) Yu, Ming; Mazor, Tali; Huang, Hui; Huang, Hsuan-Ting; Kathrein, Katie L.; Woo, Andrew; Chouinard, Candace R.; Labadorf, Adam; Akie, Thomas E.; Moran, Tyler B.; Xie, Huafeng; Zacharek, Sima; Taniuchi, Ichiro; Roeder, Robert G.; Kim, Carla; Zon, Leonard; Fraenkel, Ernest; Cantor, Alan
    Polycomb repressive complexes (PRCs) play key roles in developmental epigenetic regulation. Yet the mechanisms that target PRCs to specific loci in mammalian cells remain incompletely understood. In this study we show that Bmi1, a core component of Polycomb Repressive Complex 1 (PRC1), binds directly to the Runx1/CBFβ transcription factor complex. Genome-wide studies in megakaryocytic cells demonstrate significant chromatin occupancy overlap between the PRC1 core component Ring1b and Runx1/CBFβ and functional regulation of a considerable fraction of commonly bound genes. Bmi1/Ring1b and Runx1/CBFβ deficiencies generate partial phenocopies of one another in vivo. We also show that Ring1b occupies key Runx1 binding sites in primary murine thymocytes and that this occurs via PRC2-independent mechanisms. Genetic depletion of Runx1 results in reduced Ring1b binding at these sites in vivo. These findings provide evidence for site-specific PRC1 chromatin recruitment by core binding transcription factors in mammalian cells.
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    TIF1γ Controls Erythroid Cell Fate by Regulating Transcription Elongation
    (Elsevier BV, 2010) Bai, Xiaoying; Kim, Jonghwan; Yang, Zhongan; Jurynec, Michael J.; Akie, Thomas E.; Lee, Joseph; LeBlanc, Jocelyn; Sessa, Anna; Jiang, Hong; DiBiase, Anthony; Zhou, Yi; Grunwald, David J.; Lin, Shuo; Cantor, Alan; Orkin, Stuart; Zon, Leonard
    Recent genome-wide studies have demonstrated that pausing of RNA polymerase II (Pol II) occurred on many vertebrate genes. By genetic studies in the zebrafish tif1γ mutant moonshine we found that loss of function of Pol II-associated factors PAF or DSIF rescued erythroid gene transcription in tif1γ-deficient animals. Biochemical analysis established physical interactions among TIF1γ, the blood-specific SCL transcription complex, and the positive elongation factors p-TEFb and FACT. Chromatin immunoprecipitation assays in human CD34+ cells supported a TIF1γ-dependent recruitment of positive elongation factors to erythroid genes to promote transcription elongation by counteracting Pol II pausing. Our study establishes a mechanism for regulating tissue cell fate and differentiation through transcription elongation.
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    Erythropoietin signaling regulates heme biosynthesis
    (eLife Sciences Publications, Ltd, 2017) Chung, Jacky; Wittig, Johannes G; Ghamari, Alireza; Maeda, Manami; Dailey, Tamara A; Bergonia, Hector; Kafina, Martin D; Coughlin, Emma E; Minogue, Catherine E; Hebert, Alexander S; Li, Liangtao; Kaplan, Jerry; Lodish, Harvey F; Bauer, Daniel; Orkin, Stuart; Cantor, Alan; Maeda, Takahiro; Phillips, John D; Coon, Joshua J; Pagliarini, David J; Dailey, Harry A; Paw, Barry Htin
    Heme is required for survival of all cells, and in most eukaryotes, is produced through a series of eight enzymatic reactions. Although heme production is critical for many cellular processes, how it is coupled to cellular differentiation is unknown. Here, using zebrafish, murine, and human models, we show that erythropoietin (EPO) signaling, together with the GATA1 transcriptional target, AKAP10, regulates heme biosynthesis during erythropoiesis at the outer mitochondrial membrane. This integrated pathway culminates with the direct phosphorylation of the crucial heme biosynthetic enzyme, ferrochelatase (FECH) by protein kinase A (PKA). Biochemical, pharmacological, and genetic inhibition of this signaling pathway result in a block in hemoglobin production and concomitant intracellular accumulation of protoporphyrin intermediates. Broadly, our results implicate aberrant PKA signaling in the pathogenesis of hematologic diseases. We propose a unifying model in which the erythroid transcriptional program works in concert with post-translational mechanisms to regulate heme metabolism during normal development. DOI: http://dx.doi.org/10.7554/eLife.24767.001
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    Identification of Distal cis-Regulatory Elements at Mouse Mitoferrin Loci Using Zebrafish Transgenesis
    (American Society for Microbiology, 2011) Amigo, J. D.; Yu, M.; Troadec, M.-B.; Gwynn, B.; Cooney, J. D.; Lambert, A. J.; Chi, N. C.; Weiss, M. J.; Peters, L. L.; Kaplan, J.; Cantor, Alan; Paw, Barry Htin
    Mitoferrin 1 (Mfrn1; Slc25a37) and mitoferrin 2 (Mfrn2; Slc25a28) function as essential mitochondrial iron importers for heme and Fe/S cluster biogenesis. A genetic deficiency of Mfrn1 results in a profound hypochromic anemia in vertebrate species. To map the cis-regulatory modules (CRMs) that control expression of the Mfrn genes, we utilized genome-wide chromatin immunoprecipitation (ChIP) datasets for the major erythroid transcription factor GATA-1. We identified the CRMs that faithfully drive the expression of Mfrn1 during blood and heart development and Mfrn2 ubiquitously. Through in vivo analyses of the Mfrn-CRMs in zebrafish and mouse, we demonstrate their functional and evolutionary conservation. Using knockdowns with morpholinos and cell sorting analysis in transgenic zebrafish embryos, we show that GATA-1 directly regulates the expression of Mfrn1. Mutagenesis of individual GATA-1 binding cis elements (GBE) demonstrated that at least two of the three GBE within this CRM are functionally required for GATA-mediated transcription of Mfrn1. Furthermore, ChIP assays demonstrate switching from GATA-2 to GATA-1 at these elements during erythroid maturation. Our results provide new insights into the genetic regulation of mitochondrial function and iron homeostasis and, more generally, illustrate the utility of genome-wide ChIP analysis combined with zebrafish transgenesis for identifying long-range transcriptional enhancers that regulate tissue development.
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    The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability
    (American Association for the Advancement of Science (AAAS), 2015) Chung, Jacky; Bauer, Daniel; Ghamari, Alireza; Nizzi, C. P.; Deck, K. M.; Kingsley, P. D.; Yien, Yvette; Huston, N. C.; Chen, C.; Schultz, I. J.; Dalton, Arthur J.; Wittig, Johannes; Palis, J.; Orkin, Stuart; Lodish, H. F.; Eisenstein, R. S.; Cantor, Alan; Paw, Barry Htin
    In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. We found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mammalian target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E–binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine.
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    TMEM14C is required for erythroid mitochondrial heme metabolism
    (American Society for Clinical Investigation, 2014) Yien, Yvette; Robledo, Raymond F.; Schultz, Iman J.; Takahashi-Makise, Naoko; Gwynn, Babette; Bauer, Daniel; Dass, Abhishek; Yi, Gloria; Li, Liangtao; Hildick-Smith, Gordon J.; Cooney, Jeffrey D.; Pierce, Eric; Mohler, Kyla; Dailey, Tamara A.; Miyata, Non; Kingsley, Paul D.; Garone, Caterina; Hattangadi, Shilpa M.; Huang, Hui; Chen, Wen; Keenan, Ellen M.; Shah, Dhvanit I; Schlaeger, Thorsten; DiMauro, Salvatore; Orkin, Stuart; Cantor, Alan; Palis, James; Koehler, Carla M.; Lodish, Harvey F.; Kaplan, Jerry; Ward, Diane M.; Dailey, Harry A.; Phillips, John; Peters, Luanne L.; Paw, Barry Htin
    The transport and intracellular trafficking of heme biosynthesis intermediates are crucial for hemoglobin production, which is a critical process in developing red cells. Here, we profiled gene expression in terminally differentiating murine fetal liverderived erythroid cells to identify regulators of heme metabolism. We determined that TMEM14C, an inner mitochondrial membrane protein that is enriched in vertebrate hematopoietic tissues, is essential for erythropoiesis and heme synthesis in vivo and in cultured erythroid cells. In mice, TMEM14C deficiency resulted in porphyrin accumulation in the fetal liver, erythroid maturation arrest, and embryonic lethality due to profound anemia. Protoporphyrin IX synthesis in TMEM14Cdeficient erythroid cells was blocked, leading to an accumulation of porphyrin precursors. The heme synthesis defect in TMEM14C-deficient cells was ameliorated with a protoporphyrin IX analog, indicating that TMEM14C primarily functions in the terminal steps of the heme synthesis pathway. Together, our data demonstrate that TMEM14C facilitates the import of protoporphyrinogen IX into the mitochondrial matrix for heme synthesis and subsequent hemoglobin production. Furthermore, the identification of TMEM14C as a protoporphyrinogen IX importer provides a genetic tool for further exploring erythropoiesis and congenital anemias.
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    Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits
    (Springer Science and Business Media LLC, 2020-11-23) Choudhuri, Avik; Trompouki, Eirini; Abraham, Brian J.; Colli, Leandro M.; Kock, Kian Hong; Mallard, William; Yang, Min-Lee; Vinjamur, Divya S.; Ghamari, Alireza; Sporrij, Audrey; Hoi, Karen; Hummel, Barbara; Boatman, Sonja; Chan, Victoria; Tseng, Sierra; Nandakumar, Satish K.; Yang, Song; Lichtig, Asher; Superdock, Michael; Grimes, Seraj N.; Bowman, Teresa V.; Zhou, Yi; Takahashi, Shinichiro; Joehanes, Roby; Cantor, Alan; Bauer, Daniel; Ganesh, Santhi K.; Rinn, John; Albert, Paul S.; Bulyk, Martha; Chanock, Stephen J.; Young, Richard; Zon, Leonard
    Genome-wide association studies (GWAS) reveal genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell type-specific enhancers, but the molecular mechanism by which they cause phenotypic variation is understood in only a few instances. Here, we show that a striking proportion of enhancer-variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific master transcription factors (MTFs) and signaling transcription factors (STFs) that modulate levels of gene expression in response to extracellular signals. We find that the majority of the enhancer variants alter STF and not MTF motifs. Consequently, they perturb DNA-binding by various signaling factors including BMP/TGF-directed SMADs, WNT-induced TCFs, Hedgehog-responsive GLIs, Notch-dependent HES and affect downstream gene expression. Analysis of activity of SNPs in human CD34+ cells and eQTL analysis from the Framingham Heart Study (FHS) verifies that human alleles with disrupted STF binding lead to altered expression of genes that are upregulated during human erythroid differentiation. Our results propose that, of the RBC trait-associated variants that reside on TF binding sequences, the majority fall on DNA sequences recognized by STFs. This suggests that, in many cases, the phenotypic variation of RBC traits could be due to disruptions in STF motifs that lead to altered responsiveness to extracellular stimuli.