Circadian rhythms -- the normal ups and downs of body rhythms help organize physiological processes into a 24 hour cycle, affecting everything from body temperature, hormone levels and heart rate, to pain thresholds.

Scientists have now discovered that the combined deletion of three circadian genes, encoding the PAR bZip transcription factor protein family, results in accelerated aging and severe epilepsy in mice. Owing to the roughly 95% identity of PAR bZip proteins between mice and humans, it is anticipated that PAR bZip mutations may also underlie some forms of human epilepsy.

A copy of this important new study is being released in advance of its June 15th publication date by the journal Genes & Development (http://www.genesdev.org).

"The objective of the study was to assign physiological functions to the small family of PAR bZip transcription factors," explains Dr. Ueli Schibler, principal investigator of the study and in whose lab the first PAR bZip transcription factor was found nearly 15 years ago. The PAR bZip transcription factor family is composed of three proteins (DBP, HLF and TEF), all of which display distinct patterns of circadian accumulation: In tissues with high amplitudes of circadian clock gene expression (like the liver), PAR bZip protein levels change up to 50-fold throughout the day. However, in the brain, where clock gene expression varies little, PAR bZip protein levels barely change.

To explore the functional significance of the PAR bZip protein family, Dr. Schibler and colleagues disrupted one, two, or all three of the PAR bZip genes in mice. The single, double, and triple knock-out mice (as they are known) appear normal, but it quickly became apparent that the triple knock-ou
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Contact: Heather Cosel
coselpie@cshl.edu
Cold Spring Harbor Laboratory
7-Jun-2004