Studying the gene regulatory processes controlling stem cell development and blood cancers.
The origins of cancers and inherited blood disorders are often rooted in the dysregulation of genes, highlighting the importance of understanding the fundamental processes controlling gene expression in health and disease. However, gene regulation is highly complex due, in part, to the involvement of numerous regulatory elements and the influence of epigenetics and metabolism. Our lab is interested in understanding gene regulation in the context of stem cell development in normal and neoplastic blood cells. Through these studies, we aim to develop innovative strategies to precisely modulate gene function to aid in treating blood disorders.
Cellular identity is dependent on gene expression programs, and the maintenance of this identity relies on the proper control of gene expression in space, time and magnitude. However, gene regulation can be altered, which can cause cancer or inherited blood disorders.
Our lab is interested in understanding the fundamental processes controlling gene expression in normal and cancer stem cells. We use molecular biology, genome engineering, disease modeling, single cell technology and computational biology to study factors that regulate gene expression; specifically, we focus on non-coding genomic elements such as enhancers, epigenetics and cellular metabolism. By understanding the differences between the regulatory networks of normal and neoplastic hematopoiesis, we can learn more about the underlying causes of devasting blood disorders.
Non-coding genomic elements
About 99% of human DNA does not encode for proteins, but these non-coding genomic elements can tip the balance between health and disease. For example, retrotransposons, the repetitive transposable elements in the human genome, have long been shown to be cancer-promoting, but recent work in our laboratory uncovered a tumor suppressive role for retrotransposons in myeloid leukemia. This finding highlights the complexity of the relationship between non-coding genomic elements and human disease. A better understanding of these relationship dynamics would allow for the development of novel therapeutics.
Our laboratory is developing experimental and computational techniques to be used alongside in vitro and in vivo disease modeling which will allow us to study disease-associated non-coding genomic elements at a systems-level view. Current projects include understanding oncogenic cooperation between coding and non-coding variants in cancer pathophysiology, integrative analysis of structural variants as cancer drivers by long-reads sequencing and identifying the functional and mechanistic roles of transposable elements in cancer genomes.
We are interested in understanding how gene expression affects cell identity. It is well known that enhancers–short, cis-acting DNA sequences–can promote the transcription of target genes and, therefore, impact cell identity. While we know that cis-regulatory elements in chromatin can be modulated by transcription factors, we still do not have a complete understanding of how enhancers are regulated and how enhancers regulate spatiotemporal gene expression.
Our lab works to understand the regulatory logic of enhancer function during normal development and disease states. To accomplish this, we developed novel technologies which incorporate repurposed CRISPR/Cas9-based systems, functional genomics and optogenetics. These methods are among many techniques used in our lab that allow us to identify chromatin-based mechanisms that regulate non-coding genomic elements like enhancers and, further, to isolate these complexes and study them.
Currently, we are focusing on elucidating the roles of enhancer hijacking in cancer genomes, performing functional and mechanistic analysis of pathogenic non-coding variants and further developing technologies to assist in the dissection of genome structure and function.
Epigenetics and metabolism
A connection between epigenetics and metabolism, in the context of normal development, has been previously established. However, not much is known about how these processes interact to impact cancer progression.
Our laboratory recently showed that epigenetic alterations, such as the inactivation of EZH2, a histone methyltransferase, alters intracellular metabolism in leukemia-initiating cells, thereby providing evidence that altered epigenetics influences metabolism to promote cancer development.
We are interested in further understanding the relationship between epigenetics and metabolism in blood cells, specifically during pathological conditions. We are focusing on branched-chain amino acid metabolism in stem cell function and cancer development, metabolic control of normal and pathological erythropoiesis and identifying the metabolic dependencies of cancer stem cells as potential therapeutic targets.