Promotion and Renewals
From left to right: Scientific Director and Investigator Robb Krumlauf, PhD, Investigator Jennifer Gerton, PhD, Dean of The Graduate School and Investigator R. Scott Hawley, PhD, Investigator Ali Shilatifard, PhD, Associate Investigator Julia Zeitlinger, PhD, Investigators Joan Conaway, PhD, and Ron Conaway, PhD.
Renewed as investigator
Robb Krumlauf, PhD, has a long-term interest in the molecular signals and regulatory networks that pattern both the nervous system and overall body plan of vertebrate embryos. He is renowned for his work showing that the family of conserved DNA-binding proteins encoded by Hox genes function as master regulators that govern the formation of the hindbrain and face during mouse development. Those pioneering studies illustrate unifying principles that shape organisms as diverse as fruit flies and mammals during development, disease, and evolution.
His current research uses genomic technologies to identify downstream target genes of Hox proteins and to understand how combinations of Hox proteins specify the unique properties of tissues. Krumlauf is also investigating the origins of vertebrate head diversity by studying the sea lamprey, a jawless fish at the base of the vertebrate family tree.
In recent collaborative work with Stowers colleagues, Krumlauf surveyed how factors that change DNA structure switch Hox genes off and on in a tissue-specific manner. These studies also revealed that the SEC protein complex, which elongates RNA transcripts, is recruited to specific Hox genes to facilitate their rapid expression in response to developmental cues.
In addition to leading a research group, Krumlauf serves as Stowers’ scientific director, a position he has held since the institute was founded in 2000. During that time Stowers has recruited twenty eight faculty members and three leaders of technology centers integral to the institute’s activities.
Promoted to investigator
Jennifer Gerton, PhD, analyzes cell division focusing on factors that maintain proper chromosome number. Working primarily in yeast as a model system, Gerton studies two classes of proteins regulating the process.
One includes centromeric proteins residing at the knot of duplicated DNA strands. Last year her lab used microscopy to track a yeast protein unique to the centromeric protein core, and quantified how that protein, known as Cse4, is reshuffled during cell division. Understanding this rearrangement could suggest how cells occasionally acquire the wrong number of chromosomes, a disastrous condition associated with birth defects and cancer.
Gerton’s other focus is cohesins, proteins that encircle and connect duplicated chromosomes prior to their segregation during cell division. Cohesin mutations cause human birth defects known as cohesinopathies, which are marked by head and limb anomalies and mental retardation. Interestingly, Gerton recently reported that yeast cohesin mutants also make fewer ribosomes, the machinery used to manufacture proteins, as do cells from patients with the cohesinopathy Roberts syndrome. This unanticipated finding suggests that reduced translation may underlie the disease.
R. Scott Hawley
Renewed as investigator
Scott Hawley, PhD, studies events occurring in meiosis, the specialized cell division that allows sexual reproduction by halving chromosome number. Historically, he has focused on the myriad factors required for egg generation in the fruit fly Drosophila.
Recently, Hawley has defined signaling factors that choreograph the process, among them the protein Matrimony, which he showed blocks a major driver of cell division, the Polo kinase. As Polo is frequently hyperactive in human cancer, the work provides a novel tool to potentially antagonize cancer growth.
Hawley’s lab also recently proposed a mechanism through which the highly conserved Shaggy kinase terminates female meiosis.
At the other end of the meiosis timeline, Hawley discovered that chromosome structures called centromeres cluster as maternal and paternal chromosomes line up and swap genetic information
at the beginning of the process. Most recently, Hawley launched comparative studies of meiosis in planaria worms, which are better known for their remarkable regenerative capacity.
Inducted into the National Academy of Sciences in 2011, this year Hawley received the George W. Beadle Award for outstanding contributions to genetics research. Also known for his love of teaching, Hawley was instrumental in establishing the institute’s Graduate School, which welcomed its first class a year ago led by Hawley as dean.
Renewed as investigator
Ali Shilatifard, PhD, has been studying protein complexes that regulate gene expression during normal development and mutations associated with human cancer. His interest lies in how these complexes function and how information about their catalytic properties can be used for the treatment of human malignancies.
Shilatifard’s laboratory made history when its scientists identified the first histone H3K4 methylase in yeast. Known as Set1/COMPASS, it regulates gene expression through the methylation of histone H3, one of several DNA packaging proteins. Mammalian cells contain an extended set of six COMPASS-like complexes including Set1A/B, MLL1/2, and MLL3/4. Mutations and translocations involving MLL family members play a role in different forms of human cancer.
MLL translocations, which fuse MLL to seemingly unrelated genes, in particular, are associated with childhood leukemia, but it was unclear why. Shilatifard’s lab discovered that many of the MLL translocation partners belong to the Super Elongation Complex (SEC) and demonstrated that the translocation of MLL into SEC leads to the misrecruitment of the SEC to MLL target genes. As a result, the transcription elongation checkpoint control at these loci is perturbed, ultimately leading to leukemia.
Promoted to associate investigator
Julia Zeitlinger, PhD, investigates global changes in gene expression, or transcription, that occur as an organism develops. Using the fruit fly as a model system, her long-term goal is to detect genomic patterns predictive of human disease.
In one approach, she compared DNA regions recognized by the site-specific regulator of transcription Twist among fruit fly species. That study reported evolutionary conservation of DNA regions recognized by Twist and its interacting partners despite significant cross-species differences in DNA sequence.
Zeitlinger is also extending paradigm-shifting discoveries she made as a postdoc showing that the enzyme pol II, which copies DNA into RNA, can reside at a DNA site in an idling, or poised state prior to gene activation. She now reports that recruitment of poised pol II to genes in maturing muscle cells changes over time. That study further showed that expression of polycomb proteins, which likely restrain pol II by creating a repressive DNA structure, is tissue-specific. The work reveals an exciting cross talk between temporal and tissue-specific mechanisms to control gene expression as an organism develops.
Ron and Joan Conaway
Renewed as investigators
Ron and Joan Conaway, PhDs, study how the enzyme pol II copies, or transcribes, DNA into RNA to activate gene expression. During their twenty nine-year scientific partnership they have characterized numerous components of the basic pol II transcription machinery and defined how other protein complexes control its function.
One frequent interactor with pol II is called the Mediator, which allows pol II to either stop or go. Recently, the Conaway lab showed how one Mediator subunit, MED26, sets pol II in motion from an idling state. That work illustrated that occupancy of DNA by pol II is not sufficient for proper gene expression but that pol II must be kicked into RNA-elongating mode by the Mediator.
In other work, the Conaways showed how a membrane-bound factor ATF6α, which moves into the nucleus in response to cellular stress, recruits partners, including the Mediator and other enzymes that alter chromatin structure, to numerous gene targets to alleviate that stress. More recently they identified factors that switch on a different chromatin remodeler, ALC1. Since ALC1 is overactive in many liver cancers, the work could suggest new ways to dampen its activity.