The human genome is comprised of long strands of DNA (known as chromosomes) that need to be tightly packaged within cells. Chromosomes are compacted by wrapping around groups of dedicated packaging proteins called histones. An important consequence of this packaging is that it limits access of cellular gene expression machinery to the genetic information, and thus cells have evolved elaborate mechanisms to regulate DNA packaging. These mechanisms appear to be fundamentally conserved from humans to unicellular eukaryotes, and their improper functioning is associated with a variety of disease states including cancer, neuropsychiatric disorders, and heart disease.
My laboratory studies how these mechanisms interface with the cellular gene expression machinery. Gene expression is a complex process involving multiple steps, each of which can be subject to regulatory inputs. DNA packaging has particular consequences for early stages in the gene expression process, in which information encoded in the DNA sequence is copied into messenger RNA (a process known as transcription). Transcription involves the action of many cellular proteins. Many of these proteins directly modulate DNA packaging by introducing specific chemical modifications onto histone proteins.
We are trying to answer three basic questions: How are histone modifications formed at the right time and in the right places during transcription? What are their precise roles in regulating gene expression? How does their loss lead to abnormal patterns of gene expression and disease states? We hope that study of these questions will lead to novel therapeutic strategies for treatment of a range of diseases.