In multicellular organisms, genes must be regulated with high precision during stem-cell differentiation to achieve normal development. Pathologically, the loss of proper gene regulation caused by defects in chromatin regulatory enzymes has been found to be a driving force in cancer initiation and progression.
The Hathaway lab uses a combination of chemical-biology and cell-biology approaches to unravel the molecular mechanisms that govern gene expression. We utilize new tools wielding an unprecedented level of temporal control to visualize changes in chromatin structure and function in mammalian cells and animal models. In addition, we seek to identify small molecule inhibitors that are selective for chromatin regulatory enzymes with the potential for future human therapeutics.
The Hathaway lab is positioned along the interface between chemical biology and cell biology. Our lab uses novel chemical tools and in vivo assay systems to gain insights on how genes are epigenetically regulated in mammalian cells. Specifically, we want to understand the key molecular mechanisms responsible for complex transformations of chromatin states such as transitions between active euchromatin and repressive heterochromatin. Most of our current work focuses on the HP1-mediated heterochromatin pathway and additionally how histone acetylation state influences gene transcription. We are also developing new chemically based gene control systems capable of allele specific regulation genome wide.
One arm of the Hathaway lab at UNC focuses on further understanding the transitions between active (euchromatin) and inactive (heterochromatin) genes, with a desire to quantify the dynamics of the enzymatic machinery acting on chromatin to cause heritable changes in gene expression. These epigenetic modifications have been increasingly implicated as having a key role in cancer initiation and progression. The overarching goal of this arm of the lab is to understand the basic mechanisms underlying these complex regulatory networks, which can lead to human disease when disrupted. We have conducted high-throughput screens to identify chemical inhibitors of heterochromatin formation and memory that could have application in the treatment of cancer. Additionally, we are generating and utilizing novel chromatin in vivo assays to ask questions about gene regulatory pathways not previously addressable. The new insights for heterochromatin propagation and fidelity generated by this work will lead to generalizable models with applications to a broad range of chromatin regulatory pathways.
The second arm of the Hathaway lab uses advances we have made in chemical chromatin control systems to apply new epigenome editing technology genome wide with allele specific precision. We accomplish this by using deactivated CRISPR associated protein 9 (dCas9) to engage any desired mammalian genomic loci by specific promoter- and gene-targeting guide RNAs. We couple this technology with chemical recruitment strategies, providing the ability to recruit epigenetic regulators to sites bound by dCas9 in a dose dependent and reversible manner. This technology unearthed new insights into how chromatin landscape influences chromatin regulatory pathways. We are now pioneering this technology to control disease relevant genes in human cancer as a new therapeutic approach in collaboration with clinician scientists.
Developing projects in the lab include:
Identification of the molecular determinants of heterochromatin formation
Mechanisms leading to heterochromatin memory through cellular generations
High-throughput screens to identify small molecule inhibitors of epigenetic regulators and use of these inhibitors to gain new mechanistic insights
Controlling cellular state with novel synthetic epigenetic regulators
New chemically-based approaches to understanding and treating human cancer
Modern science is driven by collaborative projects; we are always interested in pursuing new and interesting avenues in research. Potential collaborators should contact Nate Hathaway, PhD.
Graduate Students
The Hathaway Lab is part of two graduate training programs at UNC. Students first must gain admittance to either the CBMC or BBSP programs. Motivated perspective and first-year graduate students from either program are always encouraged to contact Nate Hathaway about potential rotation projects.
Postdoctoral Fellows
We are not actively seeking postdoctoral fellows at this time. However, talented scientists with a desire to train in the lab and a strong scientific track record should contact Nate Hathaway to inquire about potential opportunities
ACCEPTING DOCTORAL STUDENTS
The Hathaway lab was established at UNC with a founding idea that the group could make a contribution to understanding dynamic epigenetic processes by using unique chemical biology approaches they pioneered. Through the combination of protein bioengineering, synthetic organic chemistry, and mammalian cell-based model systems, they have created platforms that use chemically tethered enzymatic recruitment to specific chromatin loci to produce a host of mechanistic insights. The Hathaway group also has drug discovery programs to identify new small molecules that inhibit disease relevant epigenetic pathways both for research purposes and as potential future therapeutics.
The Hathaway Lab gratefully acknowledges funding from the following sources:
Laboratory Support Grants/Awards :
National Institute of General Medical Sciences (R01)
National Institute of General Medical Sciences (Supplemental Equipment Grant)
Eshelman Institute for Innovation (Tier 3 award, Tier 2 award)
Eshelman School of Pharmacy
AACP New Investigator Award
IBM Junior Faculty Development Award
University Cancer Research Fund, University of North Carolina at Chapel Hill
North Carolina Biotechnology Center Institutional Development Grant
Selected Student Awards :
NSF Graduate Research Fellowships Program (Katie Headley)
Eshelman Institute for Innovation Student Award (Anna Chiarella)
GMB NIH T-32 (Anna Chiarella)
MiBio nIH T-32 (Katie Headley)
NC TraCS Institute Grant (Anna Chiarella)
Keystone Meeting Travel Award (Anna Chiarella)
In multicellular organisms, genes must be regulated with high precision during stem-cell differentiation to achieve normal development. Pathologically, the loss of proper gene regulation caused by defects in chromatin regulatory enzymes has been found to be a driving force in cancer initiation and progression.
