Charles Weitz

Charles J. Weitz is a chronobiologist and neurobiologist whose work primarily focuses on studying the molecular biology and genetics of circadian clocks.

At Harvard University, the Weitz lab consolidated understanding towards the transcriptional architecture of the circadian clock in Drosophila and mice models. He determined the role of the CLOCK protein, which serves to activate transcription of circadian clock genes.

He received his medical degree from the Stanford University School of Medicine in 1983. After medical school, he completed his internship in surgery/neurosurgery in 1984 at Stanford University School of Medicine. After pursuing medicine, Weitz decided to focus more on research and obtained a Ph.D. in Neuroscience from Stanford University School of Medicine in 1988. He completed his postdoctoral research under the guidance of Dr. Jeremy Nathans from 1988 to 1993 in Molecular Biology and Genetics at Johns Hopkins School of Medicine where his work focused on photoreception, investigating the genetic and molecular basis for human tritanopia.

Academic career Weitz went into teaching and currently holds the position of Robert Henry Pfeiffer Professor of Neurobiology, where he teaches graduate-level courses, including the Molecular Biology of Mammalian Circadian Clocks.

Scientific career

Role of CLOCK in feedback regulation In 1998, Weitz was one of many who helped contribute to the discovery of the role of CLOCK in feedback regulation occurring in the Drosophila model. The genes period (per) and timeless (tim) are two important genes involved in the biological clock of Drosophila. The mRNA expression of both genes occurs in circadian rhythms with approximately 24 hour periods.

Weitz also was among some of the scientists who helped to discover the role of the CLOCK protein in the mammalian circadian mechanism. Previously, the specific mechanism of how CLOCK controls and influences circadian rhythms was unknown. The research of circadian mechanisms in mammals indicated that CLOCK-BMAL1 heterodimers serve to activate the transcription of circadian clock genes such as mper1. Specifically, the heterodimers bind to E-box elements to activate transcription. A mutant CLOCK was still able to form heterodimers with BMAL1 and able to bind DNA. However, the mutation prevented activation of transcription, which indicates that CLOCK is important for the transcriptional activation of genes such as per which play a role in circadian rhythms.

Role of CRY1 and CRY2 in circadian regulation In Drosophila, CRY functions as a circadian photoreceptor by binding to TIM and inhibiting the PER-TIM negative feedback loop in response to light. However, genetic evidence has suggested that CRY may have a different role in mammals. Weitz, Griffin Jr., and Staknis investigated this hypothesis in 1999 and discovered that the two CRY homologs, CRY1 and CRY2, negatively regulate Per1 transcription by inhibiting the CLOCK-BMAL1 complex, independent of light. The regulation of Per1 is crucial for maintaining the rhythms of various physiological processes in organisms. This finding distinguishes the role of mammalian CRYs from Drosophila CRYs, which suggests that Drosophila CRYs serve as ancestral photoreceptors that act as light-dependent regulators of the circadian feedback loop, while mammalian CRYs have retained their role within the circadian feedback loop but have lost their direct photoreceptor function.

The results of Weitz and his colleagues have allowed for further investigations into the molecular mechanisms of circadian clocks. In a 2001 study by various researchers, altered behavioral rhythms and clock gene expression were observed in mice whose Period1 (Per1) gene was inactivated. This results of Weitz’s study allowed them to conclude Per1 plays an important role in peripheral and output pathways of the circadian clock. Another example is a 2000 study conducted by researchers at Medical College of Wisconsin. Using the conclusions made by Weitz’s 1999 paper, the researchers were able to use the information that changes in the level of Period2 are expected to alter levels of other clock genes, affecting the clock’s phase.

Discovery of feedback regulation by the PERIOD complex Circadian rhythms are regulated by a transcription-translation feedback loop (TTFL). In mammals, this process is crucially associated with the PER complex, formed by the combined complex of three PER and two CRY proteins. As the PER complex inhibits the expression of PER and CRY, the accumulation and degradation of the PER complex creates a negative feedback loop that helps to regulate the expression of genes involved in producing the circadian rhythm.

In 2012, Weitz, with his two lab members Kiran Padmanabhan and Maria S. Robles, investigated the feedback regulation by the PER complex. In the mouse model, they found that the PER complex contains a helicase that promotes transcriptional termination, SETX. During the negative feedback loop, RNA polymerase II accumulates near termination sites on PER and CRY genes, promoting transcription of the genes. As it reveals the structures of biomolecules previously difficult to study using traditional methods (see X-ray crystallography and nuclear magnetic resonance spectroscopy), cryo-EM is useful for gaining new insights into the structures and functions of biomolecules. It was discovered that the PER complexes exhibited quasi-spherical structures, featuring globular domains that were connected by flexible linkers.

In a 2008 paper, Katja A. Lamia, Kai-Florian Storch along with Charles Weitz discovered that a liver specific mutation to the Bmal1 gene results in low glucose levels during the fasting period of the mices’ feeding cycle. It was also discovered that there was excess glucose usage and loss of rhythmicity in the glucose regulation genes of the liver. This led to the understanding that the liver clock is important for glucose circulation and for rhythmicity of glucose export and ingestion.

Selected papers

Duong HA, Robles MS, Knutti K, Weitz CJ. A molecular mechanism for circadian clock negative feedback. Science 332, 1436-1439 (2011) Padmanabhan K, Robles MS, Westerling T, Weitz CJ. Feedback regulation of transcriptional termination by the mammalian circadian clock PERIOD complex. Science 337, 599-602 (2012) Aryal RA, Kwak PB, Tamayo AG, Chiu PL, Walz T, Weitz CJ. Macromolecular assemblies of the mammalian circadian clock. Mol. Cell (2017, in press)

Positions and honors Robert Henry Pfeiffer Professor of Neurobiology at Harvard Medical School