Bieker Laboratory

Bieker Laboratory

Bieker Laboratory

Regulation of Gene Expression During Erythropoiesis

 

Delineating the molecular events that confer the ability to express lineage-specific genes upon an initially uncommitted, pluripotent hematopoietic stem cell remain major questions in cell differentiation.  Use of an immortalized erythroid cell line as a means to isolate genes that may be important for erythroid function allowed us to identify a novel, erythroid-specific gene, which was named EKLF (erythroid Krüppel-like factor).

Biochemical, molecular, cellular, developmental, and genetic studies in mice and humans have established that EKLF is an essential component required for globin switching and completion of the definitive erythroid program. Disorders of hemoglobin expression can lead to a variety of hemoglobinopathies, including sickle cell anemia and ß–thalassemia (Cooley’s anemia). As a result, our examination of EKLF’s mechanism of action has illuminated how it regulates the globin locus, and has provided us with a way to reconstruct EKLF so that it can potentially rectify one type of hemoglobin disorder. 

Our discovery of EKLF has stimulated other investigators around the world to search for analogous genes that can work in a similar fashion to regulate unique targets in other tissues.  EKLF is now the founding member (KLF1) of a family of seventeen proteins, some of which have been directly implicated in suppression of a specific subset of cancers.

Current Projects

We are vigorously continuing the study of EKLF (KLF1) using a number of approaches, including biochemical and structure/function analyses of the EKLF protein, identification of its protein partners, examining its ability to extrinsically control erythropoiesis, and monitoring how EKLF expression itself is so precisely regulated during development.

Our most recent studies are focused on a number of areas: one, a continuing analysis of EKLF protein/protein interactions and how they result in altered transcriptional and epigenetic changes at target loci; two, on how these controls converge to regulate late events in erythropoiesis, particularly enucleation; three, on analysis of EKLF upstream regulators to help explain its exquisite tissue-restricted expression pattern, and to possibly link alteration of its expression level to aberrant red cell biology; four, on functional and phenotypic analyses of a neonatal anemia mouse mutant (Nan) that contains a mutation in one allele of EKLF; finally, on determining the mechanism by which a human mutation in EKLF leads to congenital dyserythropoietic anemia.

CV

Selected Recent Publications

L. Varricchio, A. Planutis, D. Manwani, J. Jaffray, W.B. Mitchell, A.R. Migliaccio, and J.J. Bieker, Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient, Haematologica, in press (2019). [highlighted in Hematopoiesis News]

M.N. Gnanapragasam, J.D. Crispino, A.M. Ali, R. Weinberg, R. Hoffman, A. Raza, and J.J. Bieker, Survey and evaluation of mutations in the human KLF1 transcription unit, Scientific Reports, 8, 6587 (2018).

A. Planutis, L. Xue, C.D. Trainor, M. Dangeti, K. Gillinder, M. Siatecka, L.L. Peters, A.C. Perkins, J.J. Bieker, Neomorphic effects of the neonatal anemia (Nan-EKLF) mutation contribute to deficits throughout development, Development, 144, 430-440 (2017). [highlighted as an In this Issue preview; highlighted in Hematopoiesis News]

M.N. Gnanapragasam, K.E. McGrath, S. Catherman, L. Xue, J. Palis, and J.J. Bieker, EKLF/KLF1-regulated cell cycle exit is essential for erythroblast enucleation, Blood, 128, 1631-1641 (2016). [highlighted in Hematopoiesis News]

F. Lohmann*, M. Dangeti*, S. Soni, X. Chen, A. Planutis, M.H. Baron, K. Choi, and J.J. Bieker, The DEK oncoprotein is a critical component of the EKLF/KLF1 enhancer in erythroid cells, Molecular and Cellular Biology, 35, 3726-3738 (2015). [*co-first authors] [highlighted in Exp Hem 43, 827 (15)]

S Soni , N. Pchelintsev , P.D. Adams, and J.J. Bieker, Transcription factor EKLF (KLF1) recruitment of the histone chaperone HIRA is essential for ß-globin gene expression, Proceedings of the National Academy of Sciences, 111, 13337-13342 (2014). [highlighted in Hematopoiesis News]

L. Xue, M. Galdass, M.N. Gnanapragasam, D. Manwani, and J.J. Bieker, Extrinsic and intrinsic control by EKLF (KLF1) within a specialized erythroid niche, Development, 141, 2245-2254 (2014).

Selected Reviews

M.N. Gnanapragasam and J.J. Bieker, Orchestration of late events in erythropoiesis by KLF1/EKLF, Current Opinion in Hematology, 24, 183-190 (2017).

A. Perkins, X. Xu, D.R. Higgs, G.P. Patrinos, L. Arnaud, J.J. Bieker, and S. Philipsen, “Krüppeling” erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants, Blood, 127, 1856-1862 (2016).

D. Manwani and J.J. Bieker, KLF1: when less is more, Blood, 124, 672-673 (2014).

Y. Yien and J.J. Bieker, EKLF/KLF1: a tissue-restricted integrator of transcriptional control, chromatin remodeling, and lineage determination, Molecular and Cellular Biology, 33, 4-13 (2013).

M. Siatecka and J.J. Bieker, The multifunctional role of EKLF/KLF1 during erythropoiesis, Blood, 118, 2044-2054 (2011).

J.J. Bieker, Putting a finger on the switch, Nature Genetics, 42, 733-734 (2010).

J.J. Bieker, Krüppel-like Factors: Three Fingers in Many Pies, Journal of Biological Chemistry, 276, 34355-34358 (2001).

Team

Nithya Gnanapragasam
Research Assistant Professor
nithya.gnanapragasam@mssm.edu

Kaustav Mukherjee
Postdoctoral Fellow
kaustav.mukherjee@mssm.edu
 

Li Xue
Associate Scientist
li.xue@mssm.edu
 

Antanas Planutis
Associate Researcher I
antanas.planutis@mssm.edu

Alumni

Aimola, Idowu
COORDINATOR
idowuaimola@gmail.com
Africa Center Of Excellence On Neglected Tropical Disease
Ahmadu Bello University
Department of Biochemistry
Zaria Nigeria 810000

Chen, Joy
SENIOR MANAGER, REGULATORY LEAD
jchen@diamondpharmaservices.com
Pfizer
Cambridge, MA 01239

Chen, Xiaoyong
ASSOCIATE RESEARCH SCIENTIST
xiaoyong.chen@yale.edu
Yale University School of Medicine
Dept of Pediatrics
333 Cedar St
New Haven, CT 06520

Dangeti, Mohan
R&D SYSTEMS ENGINEER
mohan.nimai@gmail.com
Ascensia Diabetes Care
Valhalla, NY  10595

Gruzglin, Eugenia
VP STRATEGY
gena.gruz@gmail.com
UNIFIED, an Omnicom Company
New York, NY

Lohmann, Felix
RESEARCH INVESTIGATOR I
felix.lohmann@novartis.com
Novartis Institutes for BioMedical Research
Basel
Switzerland

Lopingco, Tina
VP, MEDICAL STRATEGY DIRECTOR
Tina.Lopingco@prohealthmeded.com
Neon
1400 Broadway, Floor 3
New York, NY  10018

Manwani, Deepa
PROFESSOR OF PEDIATRICS
Director of Hematology
dmanwani@montefiore.org
Albert Einstein College of Medicine
Children’s Hospital at Montefiore
Pediatric Hematology/Oncology
3415 Bainbridge Ave
Bronx, NY 10467-2490

Miller, Ira J
ASSISTANT PROFESSOR
Ira_Miller@rush.edu
Rush University Medical Center
Dept of Pathology
1653 W Congress Pkwy
Chicago, IL 60612

Quadrini, Karen
RESEARCH SCIENTIST
Karen.Quadrini@iconplc.com
ICON Central Laboratories
123 Smith St.
Farmingdale, NY 11735

Siatecka, Mirka
ASSOCIATE PROFESSOR
msiatecka@amu.edu.pl
Adam Mickiewicz University
Institute of Experimental Biology
Department of Genetics
Umultowska 89
61-614 Poznań
Poland

Sengupta, Tanushri
RESEARCH ASSOCIATE
t-sengupta@northwestern.edu
Northwestern University
International Institute for Nanotechnology
2145 Sheridan Rd
Evanston, IL  60208

Soni, Shefali
ASSOCIATE PROGRAM OFFICER
ssoni@helmsleytrust.org
Helmsley Charitable Trust
IBD/Crohn’s Disease Program
230 Park Avenue
New York, NY 10169

Stranahan, Alec
ASSOCIATE, BIOTECH EQUITY RESEARCH
als2064@med.cornell.edu
Bank of America Merrill Lynch
New York, NY  10036

Yien, Yvette
ASSISTANT PROFESSOR
yyien@udel.edu
University of Delaware
Department of Biological Sciences
Newark, DE  19716

Zhang, Wenjun
SENIOR RESEARCH INVESTIGATOR II
Wenjun.Zhang@bms.com
Bristol Myers Squibb
311 Pennington Rocky Hill Rd
Pennington, NJ, 08534

Contact Us

Location
Annenberg 2584
Phone: 212-241-5067
Office: 212-241-5067
Lab: 212-241-4143
James.bieker@mssm.edu

 

Mailing Address
Mount Sinai School of Medicine
Box 1020
One Gustave L Levy Place
New York, NY  10029 

Mailing Address
Mount Sinai School of Medicine
Box 1020
One Gustave L Levy Place
New York, NY  10029