EDUCATION:
Ph.D., 1980, University of Tennessee Oakridge National Laboratory

MEMBERSHIPS:
Genetics Society of America
American Society of Microbiology
The Harvey Society

HONORS:
American Chemical Society Underwood Award
Phi Beta Kappa and Phi Beta Phi honor societies
National Research Service Award, National Cancer Institute
Special Fellow, Leukemia Society of America

EDITORIAL BOARDS:
Molecules and Cells

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We use Drosophila molecular genetics to understand how chromosome structure controls gene expression during development. Our studies have shed light on the molecular mechanisms of Cornelia de Lange syndrome, which causes diverse developmental deficits in humans.

We discovered the Nipped-B protein in a genetic screen for factors that support activation of the cut and Ultrabithorax homeobox genes by enhancers located several kilobases away from their transcription start sites. Reducing Nipped-B levels reduces cut and Ultrabithorax expression (Rollins et al. 1999; 2004; Gause et al. 2007)

Heterozygous Nipped-B mutations reduce gene expression, but homozygous Nipped-B mutations are lethal and cause defects in sister chromatid cohesion (Rollins et al. 2004). Cohesion defects are not seen in heterozygous mutants.

The role of Nipped-B in chromatid cohesion is to regulate binding of the cohesin complex to chromosomes (Fig 1). Cohesin consists of the Smc1, Smc3, Rad21 and SA proteins and has a ring-like structure. Based on work in yeast, it is proposed that cohesin encircles both sister chromatids to hold them together. Holding sister chromatids together ensures their proper distribution when the cell divides.

Reducing cohesin has the opposite effect as reducing Nipped-B, and increases cut expression (Rollins et al. 2004; Dorsett et al. 2005). Thus we hypothesize that Nipped-B controls a dynamic equilibrium of cohesin binding to chromosomes. In this model, reducing Nipped-B levels shifts the equilibrium and alters transcription of genes that bind cohesin.

Heterozygous loss-of-function mutations in the human homolog of the Nipped-B gene, Nipped-B-Like (NIPBL), cause Cornelia de Lange syndrome (CdLS) (reviewed in Dorsett 2007). CdLS patients show slow pre- and postnatal growth, mental retardation, and structural abnormalities in multiple organs and limbs. Based on our studies, we propose that the diverse symptoms of CdLS patients arise from multiple changes in gene expression.

NIPBL mutations are found in about half of all CdLS patients, and missense mutations in the human Smc1 or Smc3 cohesin subunit genes occur in about 5% of cases (reviewed in Dorsett 2007). We posit that the CdLS Smc1 missense mutations also affect gene expression by altering cohesin chromosome-binding dynamics (Deardorff et al. 2007).

To gain insights into how Nipped-B and cohesin regulate genes we mapped their binding sites in the entire Drosophila genome, and found that they bind preferentially to actively transcribed genes (Fig 2; Misulovin et al. 2007). We are now investigating how cohesin binding affects gene transcription and are using fluorescence techniques (FRAP/FRET) to examine cohesin dynamics in living cells. These studies will illuminate how Nipped-B and cohesin regulate gene expression and development.