Our Research
Challen Lab
Understanding how epigenetic marks such as histone methylation and acetylation, DNA methylation, and 5-hydroxymethylation co-ordinately act to regulate normal HSC function and how these processes go awry in hematopoietic diseases such as leukemia and lymphoma.
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 of 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 the Challen Lab’s research is understanding how epigenetic marks such as histone methylation and acetylation, DNA methylation, and 5-hydroxymethylation co-ordinately act to regulate normal HSC function and how these processes go awry in hematopoietic diseases such as leukemia and lymphoma. In order to explore these questions, we 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.
Developing new models of human blood
from basic biology into clinical applications for human blood disorders.
The functions of epigenetic mutations in hematopoietic cancers
to understand how genetic mutations in epigenetic components cause stem cell dysfunction and ultimately lead to pathogenic transformation.
Modifying the epigenome for somatic cell reprogramming
with the hypothesis is that CRISPRs can be used to edit the epigenome without off-target effects.
The role of epigenetic modifications in hematopoietic stem cell fate decision
with the goal to improve HSC function for therapies such as bone marrow transplantation.
Ongoing projects
Our lab aims to implement meaningful discoveries in basic biology to help drive novel clinical outcomes.
Developing new models of human blood
Mission
Our lab has devoted considerable time and effort to generating new genetic mouse systems to more accurately recapitulate the genetic progression of human blood cancer.
This involves mice with multiple genetic alleles of human blood cancer driver genes, with each potentially inducible in a cell-type- and temporal-dependent manner. We have also optimized CRISPR/Cas9 targeting in primary cells from human patients to translate our findings from basic research into clinical settings. Furthermore, we have developed a novel transplant system to study primary stem/progenitor cells from MPN patients in vivo using new immunodeficient mouse strains. All these complementary tools put us in a unique position to translate findings from basic biology into clinical applications for human blood disorders.
The role of epigenetic modifications in hematopoietic stem cell fate decision
Mission
Almost all cells in the human body contain the exact same DNA sequence. Obviously, a skin cell is very different from a neuron, even though they both have the exact same genes.
How a cell determines which genes are switched on or off in any given cell type of the body is controlled by epigenetic modifications. Epigenetic modifications are marks or “flags” on the DNA genome, which occur outside of changes in the DNA sequence. The combinations of the epigenetic “flags” are established in stem cells during development and tell each specific cell type which genes are to be switched on or off. Hematopoietic stem cells (HSCs) are responsible for sustaining the blood and bone marrow for the lifespan of vertebrate animals.
HSCs achieve this by a process known as asymmetric cell division, whereby each cell division of a HSC may produce one of two outcomes: (1) differentiation,which produces daughter cells that are committed to generating more blood cells, or (2) self-renewal, which allows the HSC to produce exact copies of itself so the population is maintained for as long as the animal is alive.
The decision-making process behind this HSC choice is very poorly understood, but is now recognized to be, in part, under epigenetic control. A major focus of the lab is defining the roles of epigenetic modifications in the regulation of HSC fate decisions, so that one day we might be able to manipulate them to improve HSC function for therapies such as bone marrow transplantation.
The functions of epigenetic mutations in hematopoietic cancers
Mission
Hematopoietic cancers such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) arise from genetic mutations in HSCs that impair differentiation and alter proliferation of the mutant cells, leading to a clonal expansion in the bone marrow.
High-throughput genome sequencing studies have revealed that almost half of all AML and MDS patients harbor diseases driven by genetic mutations in some component of the epigenetic machinery that affects DNA methylation or chromatin structure. Importantly, patients with mutations in epigenetic pathways have significantly worse clinical outcomes. Epigenetic modifications present attractive therapeutic targets as unlike genetic mutations, the marks are reversible, underscored by the relative effectiveness of the DNA hypomethylating agents 5-azacitidine and decitabine in a subset of MDS patients. We use complex genetic mouse models to understand how genetic mutations in epigenetic components cause stem cell dysfunction and ultimately lead to pathogenic transformation.
Modifying the epigenome for somatic cell reprogramming
Mission
Technological breakthroughs that facilitate global mapping of epigenetic marks, such as DNA methylation, histone modifications and nucleosome positioning, has unveiled how aberrant placement of these epigenetic marks is involved in human disease.
A comprehensive understanding of epigenetic mechanisms in health and disease has become a priority in biomedical research. It is now known that a number of human disorders are associated with abnormal distribution of epigenetic marks, suggesting that reversal of these modifications may present a target for therapeutic intervention. As epigenetic modifications are malleable, they are able to be dynamically transformed (unlike genetic mutations).However, no current therapy is able to alter the epigenomic landscape at particular disease-promoting loci while leaving the rest of the normal marks intact in the cell.
Current epigenetic therapies cause global epigenetic remodeling, which may provide a short-term benefit, but have long-lasting unwarranted side-effects. We are developing tools for locus-specific epigenomic remodeling. Our hypothesis is that CRISPRs can be used as finely-honed molecular scalpels to edit the epigenome without off-target effects. The technology could be easily adaptable for any disease with a characterized epigenomic defect and provide powerful tools for the study of epigenetics.
Join Our Team
Challen Lab actively recruits motivated and enthusiastic post-docs, Ph.D. students and technicians to work and assist on projects related to stem cells, epigenetics and leukemia research!
Challen Lab trainees have a 100% success rate for acquiring awards and fellowships!
Please send CV/resume, references, and research statements to Dr. Grant Challen
