Publications by authors named "Harvey Lodish"

181 Publications

Clarity on the crackdown.

Science 2021 Feb;371(6532):867

Harvey Lodish, Jianzhu Chen, and Phillip Sharp are professors in the Department of Biology at the Massachusetts Institute of Technology, Cambridge, MA, USA.

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http://dx.doi.org/10.1126/science.abh1627DOI Listing
February 2021

Over 60 Years of Experimental Hematology (without a License).

Authors:
Harvey F Lodish

Exp Hematol 2020 09 13;89:1-12. Epub 2020 Aug 13.

Whitehead Institute for Biomedical Research, Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA. Electronic address:

I am deeply honored to receive the International Society for Experimental Hematology (ISEH) 2020 Donald Metcalf Lecture Award. Although I am not a physician and have had no formal training in hematology, I have had the privilege of working with some of the top hematologists in the world, beginning in 1970 when Dr. David Nathan was a sabbatical visitor in my laboratory and introduced me to hematological diseases.  And I take this award to be given not just to me but to an exceptional group of MD and PhD trainees and visitors in my laboratory who have cloned and characterized many proteins and RNAs important for red cell development and function. Many of these projects involved taking exceptionally large risks in developing and employing novel experimental technologies. Unsurprisingly, all of these trainees have gone on to become leaders in hematology and, more broadly, in molecular cell biology and molecular medicine. To illustrate some of the challenges we have faced and the technologies we had to develop, I have chosen several of our multiyear projects to describe in some detail: elucidating the regulation of translation of α- and β-globin mRNAs and the defect in beta thalassemia in the 1970s; cloning the Epo receptor and several red cell membrane proteins in the 1980s and 1990s; and more recently, determining the function of many microRNAs and long noncoding RNAs in red cell development. I summarize how we are currently utilizing single-cell transcriptomics (scRNAseq) to understand how dividing transit-amplifying burst-forming unit erythroid progenitors balance the need for more progenitor cells with the need for terminally differentiated erythroid cells, and to identify drugs potentially useful in treating Epo-resistant anemias such as Diamond Blackfan anemia. I hope that the lessons I learned in managing these diverse fellows and projects, initially without having grants to support them, will be helpful to others who would like to undertake ambitious and important lines of research in hematology.
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http://dx.doi.org/10.1016/j.exphem.2020.08.005DOI Listing
September 2020

Phosphocholine accumulation and PHOSPHO1 depletion promote adipose tissue thermogenesis.

Proc Natl Acad Sci U S A 2020 06 17;117(26):15055-15065. Epub 2020 Jun 17.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142;

Phosphocholine phosphatase-1 (PHOSPHO1) is a phosphocholine phosphatase that catalyzes the hydrolysis of phosphocholine (PC) to choline. Here we demonstrate that the PHOSPHO1 transcript is highly enriched in mature brown adipose tissue (BAT) and is further induced by cold and isoproterenol treatments of BAT and primary brown adipocytes. In defining the functional relevance of PHOPSPHO1 in BAT thermogenesis and energy metabolism, we show that PHOSPHO1 knockout mice are cold-tolerant, with higher expression of thermogenic genes in BAT, and are protected from high-fat diet-induced obesity and development of insulin resistance. Treatment of mice with the PHOSPHO1 substrate phosphocholine is sufficient to induce cold tolerance, thermogenic gene expression, and allied metabolic benefits. Our results reveal a role of PHOSPHO1 as a negative regulator of BAT thermogenesis, and inhibition of PHOSPHO1 or enhancement of phosphocholine represent innovative approaches to manage the metabolic syndrome.
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http://dx.doi.org/10.1073/pnas.1916550117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334538PMC
June 2020

Rate of Progression through a Continuum of Transit-Amplifying Progenitor Cell States Regulates Blood Cell Production.

Dev Cell 2019 04 28;49(1):118-129.e7. Epub 2019 Feb 28.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address:

The nature of cell-state transitions during the transit-amplifying phases of many developmental processes-hematopoiesis in particular-is unclear. Here, we use single-cell RNA sequencing to demonstrate a continuum of transcriptomic states in committed transit-amplifying erythropoietic progenitors, which correlates with a continuum of proliferative potentials in these cells. We show that glucocorticoids enhance erythrocyte production by slowing the rate of progression through this developmental continuum of transit-amplifying progenitors, permitting more cell divisions prior to terminal erythroid differentiation. Mechanistically, glucocorticoids prolong expression of genes that antagonize and slow induction of genes that drive terminal erythroid differentiation. Erythroid progenitor daughter cell pairs have similar transcriptomes with or without glucocorticoid stimulation, indicating largely symmetric cell division. Thus, the rate of progression along a developmental continuum dictates the absolute number of erythroid cells generated from each transit-amplifying progenitor, suggesting a paradigm for regulating the total output of differentiated cells in numerous other developmental processes.
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http://dx.doi.org/10.1016/j.devcel.2019.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456386PMC
April 2019

FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity.

J Biol Chem 2018 12 26;293(51):19797-19811. Epub 2018 Oct 26.

the Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.

Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation. These defects were corrected with a lipid-soluble, small-molecule iron transporter, hinokitiol, in -deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter but is required for adequate mitochondrial iron import to sustain heme synthesis and iron-sulfur cluster formation during erythroid differentiation. FAM210B was also required for maximal ferrochelatase activity in differentiating erythroid cells. We propose that FAM210B functions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism.
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http://dx.doi.org/10.1074/jbc.RA118.002742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314115PMC
December 2018

Critical Issues in Diamond-Blackfan Anemia and Prospects for Novel Treatment.

Hematol Oncol Clin North Am 2018 Aug 5;32(4):701-712. Epub 2018 Jun 5.

Division of Hematology/Oncology, Dana Farber and Boston Children's Cancer and Blood Disorders Center, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address:

Diamond-Blackfan anemia (DBA) is a severe congenital hypoplastic anemia caused by mutation in a ribosomal protein gene. Major clinical issues concern the optimal management of patients resistant to steroids, the first-line therapy. Hematopoietic stem cell transplantation is indicated in young patients with an HLA-matched unaffected sibling donor, and recent results with matched unrelated donor transplants indicate that these patients also do well. When neither steroids nor a transplant is possible red cell transfusions are required, and iron loading is rapid in some DBA patients, so effective chelation is vital. Also discussed are novel treatments under investigation for DBA.
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http://dx.doi.org/10.1016/j.hoc.2018.04.005DOI Listing
August 2018

Enhanced phosphocholine metabolism is essential for terminal erythropoiesis.

Blood 2018 06 30;131(26):2955-2966. Epub 2018 Apr 30.

Whitehead Institute for Biomedical Research, Cambridge, MA.

Red cells contain a unique constellation of membrane lipids. Although much is known about regulated protein expression, the regulation of lipid metabolism during erythropoiesis is poorly studied. Here, we show that transcription of PHOSPHO1, a phosphoethanolamine and phosphocholine phosphatase that mediates the hydrolysis of phosphocholine to choline, is strongly upregulated during the terminal stages of erythropoiesis of both human and mouse erythropoiesis, concomitant with increased catabolism of phosphatidylcholine (PC) and phosphocholine as shown by global lipidomic analyses of mouse and human terminal erythropoiesis. Depletion of PHOSPHO1 impaired differentiation of fetal mouse and human erythroblasts, and, in adult mice, depletion impaired phenylhydrazine-induced stress erythropoiesis. Loss of PHOSPHO1 also impaired phosphocholine catabolism in mouse fetal liver progenitors and resulted in accumulation of several lipids; adenosine triphosphate (ATP) production was reduced as a result of decreased oxidative phosphorylation. Glycolysis replaced oxidative phosphorylation in PHOSPHO1-knockout erythroblasts and the increased glycolysis was used for the production of serine or glycine. Our study elucidates the dynamic changes in lipid metabolism during terminal erythropoiesis and reveals the key roles of PC and phosphocholine metabolism in energy balance and amino acid supply.
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http://dx.doi.org/10.1182/blood-2018-03-838516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024642PMC
June 2018

SYK kinase mediates brown fat differentiation and activation.

Nat Commun 2017 12 13;8(1):2115. Epub 2017 Dec 13.

Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA, 02142, USA.

Brown adipose tissue (BAT) metabolism influences glucose homeostasis and metabolic health in mice and humans. Sympathetic stimulation of β-adrenergic receptors in response to cold induces proliferation, differentiation, and UCP1 expression in pre-adipocytes and mature brown adipocytes. Here we show that spleen tyrosine kinase (SYK) is upregulated during brown adipocyte differentiation and activated by β-adrenergic stimulation. Deletion or inhibition of SYK, a kinase known for its essential roles in the immune system, blocks brown and white pre-adipocyte proliferation and differentiation in vitro, and results in diminished expression of Ucp1 and other genes regulating brown adipocyte function in response to β-adrenergic stimulation. Adipocyte-specific SYK deletion in mice reduces BAT mass and BAT that developed consisted of SYK-expressing brown adipocytes that had escaped homozygous Syk deletion. SYK inhibition in vivo represses β-agonist-induced thermogenesis and oxygen consumption. These results establish SYK as an essential mediator of brown fat formation and function.
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http://dx.doi.org/10.1038/s41467-017-02162-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727434PMC
December 2017

Fifty years of mentoring and advising.

Authors:
Harvey F Lodish

Mol Biol Cell 2017 Nov;28(22):2908-2910

Whitehead Institute for Biomedical Research, Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142

Advancement of science depends on thoughtfully mentoring a rare group of scientists that are highly educated, creative, and motivated-and that come from every country in the world. On the basis of my own experiences, I suggest ways to recruit top young scientists of both genders, support their development into leading researchers, and advise them about careers inside and outside of academia. Creating a family-friendly environment within the laboratory and the institution is crucial to these efforts.
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http://dx.doi.org/10.1091/mbc.E17-07-0481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662247PMC
November 2017

PD-L1 is an activation-independent marker of brown adipocytes.

Nat Commun 2017 09 21;8(1):647. Epub 2017 Sep 21.

Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.

Programmed death ligand 1 (PD-L1) is expressed on a number of immune and cancer cells, where it can downregulate antitumor immune responses. Its expression has been linked to metabolic changes in these cells. Here we develop a radiolabeled camelid single-domain antibody (anti-PD-L1 VHH) to track PD-L1 expression by immuno-positron emission tomography (PET). PET-CT imaging shows a robust and specific PD-L1 signal in brown adipose tissue (BAT). We confirm expression of PD-L1 on brown adipocytes and demonstrate that signal intensity does not change in response to cold exposure or β-adrenergic activation. This is the first robust method of visualizing murine brown fat independent of its activation state.Current approaches to visualise brown adipose tissue (BAT) rely primarily on markers that reflect its metabolic activity. Here, the authors show that PD-L1 is expressed on brown adipocytes, does not change upon BAT activation, and that BAT volume in mice can be measured by PET-CT with a radiolabeled anti-PD-L1 antibody.
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http://dx.doi.org/10.1038/s41467-017-00799-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608754PMC
September 2017

Emerging mechanisms of long noncoding RNA function during normal and malignant hematopoiesis.

Blood 2017 11 19;130(18):1965-1975. Epub 2017 Sep 19.

Whitehead Institute for Biomedical Research, Cambridge, MA; and.

Long noncoding RNAs (lncRNAs) are increasingly recognized as vital components of gene programs controlling cell differentiation and function. Central to their functions is an ability to act as scaffolds or as decoys that recruit or sequester effector proteins from their DNA, RNA, or protein targets. lncRNA-modulated effectors include regulators of transcription, chromatin organization, RNA processing, and translation, such that lncRNAs can influence gene expression at multiple levels. Here we review the current understanding of how lncRNAs help coordinate gene expression to modulate cell fate in the hematopoietic system. We focus on a growing number of mechanistic studies to synthesize emerging principles of lncRNA function, emphasizing how they facilitate diversification of gene programming during development. We also survey how disrupted lncRNA function can contribute to malignant transformation, highlighting opportunities for therapeutic intervention in specific myeloid and lymphoid cancers. Finally, we discuss challenges and prospects for further elucidation of lncRNA mechanisms.
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http://dx.doi.org/10.1182/blood-2017-06-788695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669209PMC
November 2017

Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin.

Nat Commun 2017 09 4;8(1):423. Epub 2017 Sep 4.

Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, 02142, USA.

A short half-life in the circulation limits the application of therapeutics such as single-domain antibodies (VHHs). We utilize red blood cells to prolong the circulatory half-life of VHHs. Here we present VHHs against botulinum neurotoxin A (BoNT/A) on the surface of red blood cells by expressing chimeric proteins of VHHs with Glycophorin A or Kell. Mice whose red blood cells carry the chimeric proteins exhibit resistance to 10,000 times the lethal dose (LD) of BoNT/A, and transfusion of these red blood cells into naive mice affords protection for up to 28 days. We further utilize an improved CD34+ culture system to engineer human red blood cells that express these chimeric proteins. Mice transfused with these red blood cells are resistant to highly lethal doses of BoNT/A. We demonstrate that engineered red blood cells expressing VHHs can provide prolonged prophylactic protection against bacterial toxins without inducing inhibitory immune responses and illustrates the potentially broad translatability of our strategy for therapeutic applications.The therapeutic use of single-chain antibodies (VHHs) is limited by their short half-life in the circulation. Here the authors engineer mouse and human red blood cells to express VHHs against botulinum neurotoxin A (BoNT/A) on their surface and show that an infusion of these cells into mice confers long lasting protection against a high dose of BoNT/A.
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http://dx.doi.org/10.1038/s41467-017-00448-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583347PMC
September 2017

Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation.

Proc Natl Acad Sci U S A 2017 09 1;114(38):10107-10112. Epub 2017 Sep 1.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142;

An effect of thyroid hormone (TH) on erythropoiesis has been known for more than a century but the molecular mechanism(s) by which TH affects red cell formation is still elusive. Here we demonstrate an essential role of TH during terminal human erythroid cell differentiation; specific depletion of TH from the culture medium completely blocked terminal erythroid differentiation and enucleation. Treatment with TRβ agonists stimulated premature erythroblast differentiation in vivo and alleviated anemic symptoms in a chronic anemia mouse model by regulating erythroid gene expression. To identify factors that cooperate with TRβ during human erythroid terminal differentiation, we conducted RNA-seq in human reticulocytes and identified nuclear receptor coactivator 4 (NCOA4) as a critical regulator of terminal differentiation. Furthermore, mice are anemic in perinatal periods and fail to respond to TH by enhanced erythropoiesis. Genome-wide analysis suggests that TH promotes NCOA4 recruitment to chromatin regions that are in proximity to Pol II and are highly associated with transcripts abundant during terminal differentiation. Collectively, our results reveal the molecular mechanism by which TH functions during red blood cell formation, results that are potentially useful to treat certain anemias.
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http://dx.doi.org/10.1073/pnas.1711058114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617304PMC
September 2017

The Super-Enhancer-Derived alncRNA-EC7/Bloodlinc Potentiates Red Blood Cell Development in trans.

Cell Rep 2017 06;19(12):2503-2514

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address:

Enhancer-derived RNAs are thought to act locally by contributing to their parent enhancer function. Whether large domains of clustered enhancers (super-enhancers) also produce cis-acting RNAs, however, remains unclear. Unlike typical enhancers, super-enhancers form large spans of robustly transcribed chromatin, amassing capped and polyadenylated RNAs that are sufficiently abundant to sustain trans functions. Here, we show that one such RNA, alncRNA-EC7/Bloodlinc, is transcribed from a super-enhancer of the erythroid membrane transporter SLC4A1/BAND3 but diffuses beyond this site. Bloodlinc localizes to trans-chromosomal loci encoding critical regulators and effectors of terminal erythropoiesis and directly binds chromatin-organizing and transcription factors, including the chromatin attachment factor HNRNPU. Inhibiting Bloodlinc or Hnrnpu compromises the terminal erythropoiesis gene program, blocking red cell production, whereas expressing Bloodlinc ectopically stimulates this program and can promote erythroblast proliferation and enucleation in the absence of differentiation stimuli. Thus, Bloodlinc is a trans-acting super-enhancer RNA that potentiates red blood cell development.
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http://dx.doi.org/10.1016/j.celrep.2017.05.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013260PMC
June 2017

Erythropoietin signaling regulates heme biosynthesis.

Elife 2017 05 29;6. Epub 2017 May 29.

Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.

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, , 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.
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http://dx.doi.org/10.7554/eLife.24767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478267PMC
May 2017

Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease.

Proc Natl Acad Sci U S A 2017 03 7;114(12):3157-3162. Epub 2017 Mar 7.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142;

Current therapies for autoimmune diseases rely on traditional immunosuppressive medications that expose patients to an increased risk of opportunistic infections and other complications. Immunoregulatory interventions that act prophylactically or therapeutically to induce antigen-specific tolerance might overcome these obstacles. Here we use the transpeptidase sortase to covalently attach disease-associated autoantigens to genetically engineered and to unmodified red blood cells as a means of inducing antigen-specific tolerance. This approach blunts the contribution to immunity of major subsets of immune effector cells (B cells, CD4 and CD8 T cells) in an antigen-specific manner. Transfusion of red blood cells expressing self-antigen epitopes can alleviate and even prevent signs of disease in experimental autoimmune encephalomyelitis, as well as maintain normoglycemia in a mouse model of type 1 diabetes.
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http://dx.doi.org/10.1073/pnas.1701746114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373388PMC
March 2017

US immigration order strikes against biotech.

Authors:
Jeremy M Levin Steven H Holtzman John Maraganore Paul J Hastings Ron Cohen Bassil Dahiyat Julian Adams Chris Adams Brett Ahrens Jeff Albers Mara G Aspinall James E Audia Martin Babler Peter Barrett Zoe Barry Nessan Bermingham Stephen Bloch Robert I Blum Paul B Bolno Michael W Bonney Bruce Booth Daniel M Bradbury Steven K Brauer Brook Byers Pablo J Cagnoni Brian M Cali Isaac Ciechanover Chip Clark Michael D Clayman Jeff L Cleland Paula Cobb Ron Cooper Mark G Currie John Diekman Eric L Dobmeier Doug Doerfler Elizabeth Lr Donley Deborah Dunsire Matthew During Jens W Eckstein Eric Elenko Neil A Exter Jonathan J Fleming Gregory J Flesher Jean-Francois Formela Robert Forrester Cedric Francois Heather Franklin Mason W Freeman Howard Furst Leonard Patrick Gage Nicholas Galakatos Brian M Gallagher James A Geraghty Simba Gill David V Goeddel Mark A Goldsmith Maxine Gowen Vikas Goyal Tom Graney David Grayzel Barry Greene Paul Grint J C Gutierrez-Ramos Bill Haney Tuan Ha-Ngoc Tim Harris Faheem Hasnain Yujiro Steve Hata Peter Hecht Leslie Henshaw Rich Heyman Herve Hoppenot H Robert Horvitz Thomas E Hughes Wende S Hutton Stephen T Isaacs Annalisa Jenkins Jeff Jonker Jeff Kaplan Perry Karsen Jeb Keiper Jean Kim Jeff Kindler Rachel King Vanessa King Nina Kjellson Scott Koenig Gerhard Koenig Peter Kolchinsky Paul Laikind Robert Bob Langer John J Lee Jonathan S Leff Bruce A Leicher Nick Leschly Andrew Levin Mark Levin Arnold J Levine Alan Levy David R Liu Harvey F Lodish Uri Lopatin Ted W Love Guy Macdonald Gail J Maderis Ankit Mahadevia Nagesh K Mahanthappa Joel F Martin Alex Martin W Eddie Martucci James G McArthur Corey M McCann Sean A McCarthy C Geoffrey McDonough John Mendlein Larry Miller Diego Miralles Kenneth I Moch Bob More Andrew G Myers Michael A Narachi Amir Nashat Wendy Nelson William J Newell Bernat Olle John E Osborn Julia C Owens Atul Pande Stelios Papadopoulos H Stewart Parker Kush M Parmar Matthew R Patterson Steve M Paul Rob Perez Matthew Perry Cary G Pfeffer Mike Powell Mark Pruzanski Dennis J Purcell Amit Rakhit Kartik Ramamoorthi William Rastetter Adrian Ad Rawcliffe Laurence E Reid Ron C Renaud Jason P Rhodes William J Rieflin Chad Robins Scott M Rocklage Michael Rosenblatt Jonathan G Rosin William J Rutter Saurabh Saha Camille Samuels Vicki L Sato George Scangos John A Scarlett David Schenkein Stuart L Schreiber Andrew Schwab Paul Sekhri Rajeev Shah Thomas Shenk Clay B Siegall Nick J Simon Nancy Simonian Jeff Stein Michael Su Mary T Szela Marco Taglietti Nina Tandon Henri Termeer Nancy A Thornberry Martin Tolar Richard Ulevitch Akshay K Vaishnaw Anne VanLent Martin Varsavsky George P Vlasuk Michel Vounatsos Samuel G Waksal Neil Warma Ryan J Watts Yaron Werber Christoph Westphal Wendell Wierenga Doug E Williams Lewis Rusty Williams Kleanthis G Xanthopoulos Daphne Zohar Sandford Sandy Zweifach

Nat Biotechnol 2017 03;35(3):204-206

Nuvelution Pharmaceuticals, Inc., South San Francisco, California, USA.

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http://dx.doi.org/10.1038/nbt.3824DOI Listing
March 2017

Unclogging sickle cell anaemia.

Nat Rev Mol Cell Biol 2017 04 1;18(4):214. Epub 2017 Mar 1.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

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http://dx.doi.org/10.1038/nrm.2017.17DOI Listing
April 2017

Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors.

Sci Transl Med 2017 02;9(376)

Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.

Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA.
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http://dx.doi.org/10.1126/scitranslmed.aah5645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501179PMC
February 2017

JAK2 V617F stimulates proliferation of erythropoietin-dependent erythroid progenitors and delays their differentiation by activating Stat1 and other nonerythroid signaling pathways.

Exp Hematol 2016 Nov 26;44(11):1044-1058.e5. Epub 2016 Jul 26.

Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA; Departments of Biology and Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA. Electronic address:

JAK2 V617F is a mutant-activated JAK2 kinase found in most polycythemia vera (PV) patients; it skews normal proliferation and differentiation of hematopoietic stem and progenitor cells and simulates aberrant expansion of erythroid progenitors. JAK2 V617F is known to activate some signaling pathways not normally activated in mature erythroblasts, but there has been no systematic study of signal transduction pathways or gene expression in erythroid cells expressing JAK2 V617F undergoing erythropoietin (Epo)-dependent terminal differentiation. Here we report that expression of JAK2 V617F in murine fetal liver Epo-dependent progenitors allows them to divide approximately six rather than the normal approximately four times in the presence of Epo, delaying their exit from the cell cycle. Over time, the number of red cells formed from each Epo-dependent progenitor increases fourfold, and these cells eventually differentiate into normal enucleated reticulocytes. We report that purified fetal liver Epo-dependent progenitors express many cytokine receptors additional to the EpoR. Expression of JAK2 V617F triggers activation of Stat5, the only STAT normally activated by Epo, as well as activation of Stat1 and Stat3. Expression of JAK2 V617F also leads to transient induction of many genes not normally activated in terminally differentiating erythroid cells and that are characteristic of other hematopoietic lineages. Inhibition of Stat1 activation blocks JAK2 V617F hyperproliferation of erythroid progenitors, and we conclude that Stat1-mediated activation of nonerythroid signaling pathways delays terminal erythroid differentiation and permits extended cell divisions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083198PMC
http://dx.doi.org/10.1016/j.exphem.2016.07.010DOI Listing
November 2016

TGF-β inhibitors stimulate red blood cell production by enhancing self-renewal of BFU-E erythroid progenitors.

Blood 2016 12 24;128(23):2637-2641. Epub 2016 Oct 24.

Whitehead Institute for Biomedical Research, Cambridge, MA.

Burst-forming unit erythroid progenitors (BFU-Es) are so named based on their ability to generate in methylcellulose culture large colonies of erythroid cells that consist of "bursts" of smaller erythroid colonies derived from the later colony-forming unit erythroid progenitor erythropoietin (Epo)-dependent progenitors. "Early" BFU-E cells forming large BFU-E colonies presumably have higher capacities for self-renewal than do "late" BFU-Es forming small colonies, but the mechanism underlying this heterogeneity remains unknown. We show that the type III transforming growth factor β (TGF-β) receptor (TβRIII) is a marker that distinguishes early and late BFU-Es. Transient elevation of TβRIII expression promotes TGF-β signaling during the early BFU-E to late BFU-E transition. Blocking TGF-β signaling using a receptor kinase inhibitor increases early BFU-E cell self-renewal and total erythroblast production, suggesting the usefulness of this type of drug in treating Epo-unresponsive anemias.
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http://dx.doi.org/10.1182/blood-2016-05-718320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146747PMC
December 2016

A Long Noncoding RNA lincRNA-EPS Acts as a Transcriptional Brake to Restrain Inflammation.

Cell 2016 Jun;165(7):1672-1685

Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA; Centre for Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, NTNU, 7491 Trondheim, Norway. Electronic address:

Long intergenic noncoding RNAs (lincRNAs) are important regulators of gene expression. Although lincRNAs are expressed in immune cells, their functions in immunity are largely unexplored. Here, we identify an immunoregulatory lincRNA, lincRNA-EPS, that is precisely regulated in macrophages to control the expression of immune response genes (IRGs). Transcriptome analysis of macrophages from lincRNA-EPS-deficient mice, combined with gain-of-function and rescue experiments, revealed a specific role for this lincRNA in restraining IRG expression. Consistently, lincRNA-EPS-deficient mice manifest enhanced inflammation and lethality following endotoxin challenge in vivo. lincRNA-EPS localizes at regulatory regions of IRGs to control nucleosome positioning and repress transcription. Further, lincRNA-EPS mediates these effects by interacting with heterogeneous nuclear ribonucleoprotein L via a CANACA motif located in its 3' end. Together, these findings identify lincRNA-EPS as a repressor of inflammatory responses, highlighting the importance of lincRNAs in the immune system.
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http://dx.doi.org/10.1016/j.cell.2016.05.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289747PMC
June 2016

Efficient CRISPR-Cas9 mediated gene disruption in primary erythroid progenitor cells.

Haematologica 2016 06 11;101(6):e216-9. Epub 2016 Mar 11.

Whitehead Institute for Biomedical Research, Cambridge, MA, USA Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

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http://dx.doi.org/10.3324/haematol.2015.135723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013953PMC
June 2016

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling.

Proc Natl Acad Sci U S A 2015 Oct 5;112(42):E5679-88. Epub 2015 Oct 5.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.
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http://dx.doi.org/10.1073/pnas.1517932112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620870PMC
October 2015

PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal.

Nature 2015 Jun 11;522(7557):474-7. Epub 2015 May 11.

1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-α agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.
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http://dx.doi.org/10.1038/nature14326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498266PMC
June 2015

De Novo Reconstruction of Adipose Tissue Transcriptomes Reveals Long Non-coding RNA Regulators of Brown Adipocyte Development.

Cell Metab 2015 May 23;21(5):764-776. Epub 2015 Apr 23.

Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.

Brown adipose tissue (BAT) protects against obesity by promoting energy expenditure via uncoupled respiration. To uncover BAT-specific long non-coding RNAs (lncRNAs), we used RNA-seq to reconstruct de novo transcriptomes of mouse brown, inguinal white, and epididymal white fat and identified ∼1,500 lncRNAs, including 127 BAT-restricted loci induced during differentiation and often targeted by key regulators PPARγ, C/EBPα, and C/EBPβ. One of them, lnc-BATE1, is required for establishment and maintenance of BAT identity and thermogenic capacity. lnc-BATE1 inhibition impairs concurrent activation of brown fat and repression of white fat genes and is partially rescued by exogenous lnc-BATE1 with mutated siRNA-targeting sites, demonstrating a function in trans. We show that lnc-BATE1 binds heterogeneous nuclear ribonucleoprotein U and that both are required for brown adipogenesis. Our work provides an annotated catalog for the study of fat depot-selective lncRNAs and establishes lnc-BATE1 as a regulator of BAT development and physiology.
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http://dx.doi.org/10.1016/j.cmet.2015.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429916PMC
May 2015

The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability.

Sci Signal 2015 Apr 14;8(372):ra34. Epub 2015 Apr 14.

Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

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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http://dx.doi.org/10.1126/scisignal.aaa5903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402725PMC
April 2015

Genome-wide association study follow-up identifies cyclin A2 as a regulator of the transition through cytokinesis during terminal erythropoiesis.

Am J Hematol 2015 May 5;90(5):386-91. Epub 2015 Feb 5.

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Whitehead Institute for Biomedical Research, Cambridge, Massachusetts; Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany; Charité-Universitätsmedizin Berlin, Berlin, Germany.

Genome-wide association studies (GWAS) hold tremendous promise to improve our understanding of human biology. Recent GWAS have revealed over 75 loci associated with erythroid traits, including the 4q27 locus that is associated with red blood cell size (mean corpuscular volume). The close linkage disequilibrium block at this locus harbors the CCNA2 gene that encodes cyclin A2. CCNA2 mRNA is highly expressed in human and murine erythroid progenitor cells and regulated by the essential erythroid transcription factor GATA1. To understand the role of cyclin A2 in erythropoiesis, we have reduced expression of this gene using short hairpin RNAs in a primary murine erythroid culture system. We demonstrate that cyclin A2 levels affect erythroid cell size by regulating the passage through cytokinesis during the final cell division of terminal erythropoiesis. Our study provides new insight into cell cycle regulation during terminal erythropoiesis and more generally illustrates the value of functional GWAS follow-up to gain mechanistic insight into hematopoiesis.
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http://dx.doi.org/10.1002/ajh.23952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409486PMC
May 2015

Accommodating family life: mentoring future female faculty members.

Authors:
Harvey F Lodish

Trends Cell Biol 2015 Mar 15;25(3):109-11. Epub 2015 Jan 15.

Whitehead Institute for Biomedical Research, Departments of Biology and Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge MA 012142, USA. Electronic address:

The demands of family life are crucial factors in successfully retaining women in science. Retention efforts should focus on creating a family-friendly environment within the laboratory and the institute. Based on my own experiences, I suggest ways to attract top young scientists and support their development into leading researchers.
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http://dx.doi.org/10.1016/j.tcb.2014.12.007DOI Listing
March 2015

Long non-coding RNAs as regulators of the endocrine system.

Nat Rev Endocrinol 2015 Mar 6;11(3):151-60. Epub 2015 Jan 6.

Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, 8 College Road, 169857, Singapore.

Long non-coding RNAs (lncRNAs) are a large and diverse group of RNAs that are often lineage-specific and that regulate multiple biological functions. Many are nuclear and are essential parts of ribonucleoprotein complexes that modify chromatin segments and establish active or repressive chromatin states; others are cytosolic and regulate the stability of mRNA or act as microRNA sponges. This Review summarizes the current knowledge of lncRNAs as regulators of the endocrine system, with a focus on the identification and mode of action of several endocrine-important lncRNAs. We highlight lncRNAs that have a role in the development and function of pancreatic β cells, white and brown adipose tissue, and other endocrine organs, and discuss the involvement of these molecules in endocrine dysfunction (for example, diabetes mellitus). We also address the associations of lncRNAs with nuclear receptors involved in major hormonal signalling pathways, such as estrogen and androgen receptors, and the relevance of these associations in certain endocrine cancers.
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http://dx.doi.org/10.1038/nrendo.2014.229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376378PMC
March 2015