Grant Challen, Ph.D.

Assistant Professor
Internal Medicine
Oncology

Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Molecular Genetics and Genomics Program
Computational and Systems Biology Program

  • 314-362-0987

  • 314-362-0986

  • 314-747-2797

  • 8056

  • McDonnell Sciences Room 558

  • gchallen@WUSTL.EDU

  • http://oncology.wustl.edu/people/faculty/Challen/Challen_Bio.html

  • Hematopoietic stem cells, Leukemia stem cells, Epigenetic modifications

  • Understanding the genetic and epigenetic mechanisms that regulate normal and leukemic stem cells

Research Abstract:

Hematopoietic stem cells (HSCs) reside in the bone marrow and are defined by their capacity for lifetime maintenance of the blood and bone marrow, achieved through their differentiation into the myriad cellular components, as well as their ability to generate additional stem cells via self-renewal. The mechanisms that instruct the fate of stem cells toward differentiation versus self-renewal are still relatively poorly understood. A number of transcription factors have been identified as critical for HSC maintenance and self-renewal; however, we have little insight into how these factors are orchestrated by epigenetic mechanisms to ensure blood homeostasis. The central theme of my research is understanding how epigenetic marks such as histone methylation and acetylation, DNA methylation, and 5-hydroxymethylation coordinately act to regulate normal HSC function and how these processes go awry in hematopoietic diseases such as leukemia and lymphoma. We also use various mouse genetic models to study the roles of genetic mutations of different components of the epigenetic machinery in cancers of the blood and bone marrow.

Ongoing projects in the lab include

* The role of DNA methylation in hematopoietic stem cell fate decision
* The functions of epigenetic mutations in leukemias and lymphomas
* Modifying the epigenome for somatic cell reprogramming

Selected Publications:

Celik H, Mallaney C, Kothari A, Ostrander EL, Eultgen E, Martens A, Miller CA, Hundal J, Klco JM and Challen GA (2015). “Enforced Differentiation of Dnmt3a-null Bone Marrow Leads to Failure with c-Kit Mutations Driving Leukemic Transformation.” Blood, 125(4): 619-628. NIHMS ID: in process.

Challen GA, Sun D, Mayle A, Jeong M, Luo M, Rodriguez B, Mallaney C, Celik H, Yang L, Xia Z, Cullen S, Berg J, Zheng Y, Darlington GJ, Li W and Goodell MA (2014). “Dnmt3a and Dnmt3b have Overlapping and Distinct Functions in Hematopoietic Stem Cells.” (cover article) Cell Stem Cell, 15(3): 350-364. PMCID: PMC4163922.

Matatall K, Shen K, Challen GA and King KY (2014). “Type II Interferon Promotes Differentiation of Myeloid-Biased Hematopoietic Stem Cells.” Stem Cells, 32(11): 3023-3030. PMC Journal – In Process.

Mallaney C, Kothari A, Martens A, Challen GA (2014). “Clonal-level responses of functionally distinct hematopoietic stem cells to trophic factors.” Experimental Hematology, 42(4):317-327. PMCID: PMC4004675.

Jeong M, Luo M, Sun D, Challen GA, Godley L, Rao A, Li W and Goodell MA (2014). “Large ancient DNA segments with low methylation maintained by 5-hydroxymethylcytosine and Dnmt3a.” Nature Genetics, 46(1):17-23. PMCID: PMC3920905.

Challen GA, Sun D, Jeong M, Luo M, Jelinek J, Berg JS, Bock C, Vasanthakumar A, Gu H, Xi Y, Liang S, Lu Y, Darlington GJ, Meissner A, Issa JP, Godley LA, Li W, and Goodell MA (2011). “Dnmt3a is Essential for Hematopoietic Stem Cell Differentiation.” Nature Genetics 44(1): 23-31. PMCID: PMC3637952

Rossi L, Challen GA, Sirin O, Lin KK, Goodell MA. (2011) “Hematopoietic Stem Cell Characterization and Isolation.” Methods Mol Biol. 750: 47-59. PMCID: PMC3621966.

Challen GA, Boles NC, Chambers SM and Goodell MA (2010). “Distinct Hematopoietic Stem Cell Subtypes Are Differentially Regulated by TGFb1.” Cell Stem Cell, 6:265-278. PMCID: PMC2837284

Challen GA and Goodell MA (2010). “Runx1 Isoforms Show Differential Expression Patterns During Development but Appear to be Functionally Redundant in Adult Hematopoietic Stem Cells.” Experimental Hematology, 38:403-416 (cover article). PMCID: PMC2854264

Challen GA, Boles N, Lin KK and Goodell MA (2009). “Mouse Hematopoietic Stem Cell Identification And Analysis.” Cytometry A. 75:14-24. PMCID: PMC2640229

Last Updated: 7/1/2015 9:13:39 AM

Model for Dnmt3a action in HSCs. “HSC genes” are mostly unmethylated and expressed in normal HSCs (left). Upon receiving a signal to differentiate, Dnmt3a methylates and silences these regions to permit lineage commitment. This is associated with a loss of H3K4me3. These genes are then repressed in B-cells. Dnmt3a-KO HSCs (right) cannot silence these “HSC genes” so upon receiving a stimulus to differentiate, these genes remain expressed due to lack of methylation and elevated H3K4me3. Upon cell division, the HSC self-renewal pathway remains the default state for Dnmt3a-KO HSCs resulting in their accumulation in the bone marrow. Of the few Dnmt3a-KO HSCs that do differentiate, their progeny show incomplete methylation and repression of “HSC genes.” Nat Genet 2011 Dec 4;44(1):23-31
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