Local Chromatin Composition Impacts Chromosome Folding Between Distant Genomic Loci

Kyle Eagen

Kyle P. Eagen, PhD
Feinberg Fellow, Northwestern University
Feinberg School of Medicine
Department of Biochemistry and Molecular Genetics
Simpson Querrey Center for Epigenetics
Wednesday, May 8| 4:00 pm
Ryan 4003

 

Abstract

Delineating how chromosomes fold at length scales beyond one megabase remains obscure relative to smaller-scale folding into self-associating domains (TADs), loops, and nucleosomes. We find that a fusion oncoprotein, which epigenetically re-writes large domains of chromatin, initiates distant interactions between loci separated by tens to hundreds of megabases, with notable effects on gene activity. These interactions occur both within and between chromosomes and are equivalent to TAD-TAD interactions. We find that genes within domains contacting other domains are more highly expressed than genes devoid of domain-domain interactions. In a patient-derived cell line, these interactions can be pharmacologically modulated with a small-molecule proteolysis targeting chimera (PROTAC) resulting in changes in gene expression that reflect loss or gain of domain-domain interactions. Our integrated structure-function approach thus reveals a link between megabase-scale chromosome folding, local chromatin composition, and gene regulation, and also indicates the potential of altering chromosome structure for the treatment of human disease.

Biography

Kyle Eagen was an undergraduate at Cornell University where he received his bachelor’s degree in Biological Sciences with a concentration in Biochemistry while studying the rapid chemical kinetics of neurotransmitter receptors in the lab of George Hess. He moved to California in 2008 for graduate studies at Stanford University. At Stanford, he worked with Roger Kornberg studying chromatin and chromosome structure. After completing his Ph.D. in Biophysics, Dr. Eagen began his independent career in 2017 as the inaugural Feinberg Fellow at the Northwestern University Feinberg School of Medicine within the Department of Biochemistry and Molecular Genetics.

Academic Focus

The molecular basis of DNA folding within interphase nuclei and mitotic chromosomes is one of the great mysteries of biology and has fascinated scientists for over a century. An increasing number of human diseases, from congenital malformations to cancer, have been linked to DNA misfolding, hastening the need to resolve this mystery. We combine concepts and approaches from structural biology and biochemistry with methods and analytical tools from molecular biology and genomics to determine the…[Read full text]The molecular basis of DNA folding within interphase nuclei and mitotic chromosomes is one of the great mysteries of biology and has fascinated scientists for over a century. An increasing number of human diseases, from congenital malformations to cancer, have been linked to DNA misfolding, hastening the need to resolve this mystery. We combine concepts and approaches from structural biology and biochemistry with methods and analytical tools from molecular biology and genomics to determine the structural and biochemical basis of chromatin folding and chromosome condensation. Our long-term goal is to contribute fundamental knowledge about the nature of DNA folding and elucidate general principles of chromatin and chromosome organization that will enable insights into human disease processes and serve as a basis for developing targeted, precise therapeutics.

 

Sponsored by the Chicago Region Physical Sciences-Oncology Center NCI U54CA193419