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= Charles J. Weitz =

Charles “Chuck” Weitz is an American neurobiologist and chronobiologist who is currently the Robert Henry Pfeiffer Professor of Neurobiology at Harvard Medical School. He is most renowned for his work on the transcription translation feedback loop (TTFL) in Drosophila. Weitz’s current lab at Harvard University focuses on understanding the molecular biology and genetics of circadian clocks. Weitz’s work seeks to understand the integrated functions of multiprotein machines that drive the biological clock.

From 2012 to 2017, Weitz has been doing research on the macromolecular assemblies of clock genes and proteins. Within this research, he has furthered the understanding of the protein motifs and structures responsible for the exact interactions of the proteins within the TTFL that governs the circadian rhythm of organisms.

Biography
Weitz was born in Detroit, Michigan in 1956 and moved to Los Angeles, California when he was seven. He finished middle school and high school in California and was named a Governor’s Scholar in the State of California in 1972.

Education
Weitz graduated with a Bachelor of Arts from Harvard University in 1978 with a concentration in philosophy. He then received his M.D. from Stanford University School of Medicine in 1983 and completed a postdoctoral surgical internship in neuroscience at the Stanford Medical Center in 1984. He received his Ph.D. in Neurosciences in 1988 under the mentorship of Avram Goldstein. After graduation, Weitz continued his research as a postdoctoral fellow of molecular biology and genetics at Johns Hopkins University School of Medicine under Jeremy Nathans.

Career
After his postdoctoral research, Weitz became an assistant professor of neurobiology at Harvard Medical School in 1993, an associate professor of neurobiology in 1998, and since 2003, has served as the Robert Henry Pfeiffer Professor of Neurobiology. As the end of his postdoctoral fellowship neared, he decided to start working on circadian clocks, specifically focusing on how organisms keep time at the molecular level. While there was already a strong genetic foundation and basic knowledge that these biological clocks were built from a cell-autonomous molecular feedback loop, there wasn’t much known about the specific mechanism or the mammalian clock genes and proteins involved. His research has identified specific clock genes and proteins involved in the TTFL and his lab currently researches the various molecular components of circadian clocks and the molecular pathways involved with the central circadian clock in the suprachiasmatic nucleus (SCN), a small portion of the hypothalamus, to dictate various physiological rhythms in behavior. Weitz’s lab has recently started genetically analyzing circadian physiological functions of the brain, retina, and other peripheral tissues.

Timing of PER’s nuclear entry
In 1995, Charles Weitz, alongside colleague Nicholas Gekakis, discovered that the dimerization of TIM, a protein produced by the timeless gene in Drosophila that's essential for maintaining circadian rhythms, PER, a protein produced by the period gene in Drosophila, at PAS domains determined the timing of PER’s nuclear entry in Drosophila. This was his first contribution of many to the field of chronobiology.

Closing of the circadian loop
Next, in 1998, Weitz discovered the machinery involved in the negative feedback loop that regulates the Drosophila circadian clock. Weitz and his colleagues found that the Drosophila CLOCK gene, a gene encoding a basic helix-loop-helix-PAS transcription factor assumed to be responsible for circadian rhythms, induces transcription of the circadian rhythm genes period and timeless. Weitz further advanced understandings of biological machinery underlying the fundamental aspects of circadian clocks by discovering that a heterodimer consisting of dCLOCK and a Drosophila homolog of BMAL1, a human gene encoding for a transcription factor in the TTFL which is necessary to maintain a regular circadian rhythm in humans, acting through an E Box sequence in the promoter of period drive the expression of period and timeless. When period and timeless are transcribed and subsequently translated into protein, they dimerize, enter the nucleus, and inhibit dCLOCK’s activity. Ultimately, Weitz’s discoveries were fundamental in completing the knowledge of the entire circadian negative feedback loop. Furthermore, a mutant CLOCK from the dominant-negative CLOCK allele and BMAL1 formed heterodimers that interacted with DNA, but failed to induce transcription. Thus, Weitz and others concluded that CLOCK-BMAL1 heterodimers drive the transcription of the per gene in Drosophila.

Role of cryptochrome
In 1999, Weitz helped discover the role of the photopigment cryptochrome, a gene encoding CRY in Drosophila. Weitz, along with his colleagues, reported that dCRY, Drosophilan CRY, selectively sequesters dTIM, Drosophilan timeless, and degrades it when drosophila are exposed to light in the subjective night. This discovery is important for understanding how all organisms entrain to light-dark cycles in the wild and provided a basic guide for research into other organisms. Furthermore, in 1999 Weitz, discovered that the activity of CRY1 and CRY2 in mammals was light-independent, and contrary to dCRY CRY1 and CRY2, were not photopigments. This discovery provided evidence that Drosophila and mammals follow different entrainment pathways.

Mechanism behind negative feedback loop: TRAP150
After discovering the existence of the feedback loop in 1998, Weitz, along with other chronobiologists in 2013, studied the specific mechanism by which proteins inhibit their own transcription. He found that mouse BMAL1 includes thyroid hormone receptor-associated protein-150 (TRAP150), which is a selective coactivator for CLOCK-BMAL1, oscillating under its control. It promotes binding to target genes and links CLOCK-BMAL1 to the transcriptional machinery at target promoters. Ablation of TRAP150 led to low amplitude and extended periods suggesting it may be a positive clock element. Weitz and his team concluded that TRAP150 defines a positive feedback loop inside of the clock, introducing a potential mechanism for the reactivation of circadian transcription.

SCN and behavior
In 2001 and later in 2006, Weitz focused on the output signals of the SCN and the roles of the SCN in secreting regulatory factors of locomotion and behavior. He found that epidermal growth factor (EGF) receptors in neurons in the hypothalamus mediate interact with transforming growth factor-alpha (TGF), which is secreted rhythmically by the SCN. Weitz found this signaling pathway to help regulate daily activity in locomotion. Weitz later found that cardiotrophine-like cytokine (CLC), a cytokine secreted rhythmically by a subpopulation of SCN, also plays a role in daily locomotion behavior in mammals.

Discovery of Clock-Interacting Protein
In 2007, Weitz and other chronobiologists discovered that Clock-Interacting Protein (CIPC) is an additional negative-feedback regulator of the mammalian circadian clock. They found that CIPC exhibits 24-hour rhythm in expression in multiple tissues and that it, more importantly, inhibits CLOCK-BMAL1 activity. In addition, they found that depletion of CIPC results in a shortened period length. This discovery is important because it reveals not only another aspect of the circadian clock machinery but that the circadian clock is complex and that there is much more to discover.

Role of BMAL1 in homeostasis
In 2011, Weitz and colleagues found that the BMAL1 circadian clock gene is required in the pancreas for glucose homeostasis and insulin secretion. This conclusion provides a glimpse into the applications of circadian clocks outside of sleeping and locomotion, as clocks are most likely located in all cell types. Mutant mice that did not have the clock genes in the pancreas showed severe glucose intolerance and could not produce insulin normally.

Macromolecular components of circadian feedback loop
Most recently, in 2017, Weitz examined the macromolecular assemblies of the mammalian circadian clock. Looking at a mouse liver nuclei, Weitz and his colleagues found all three PERs, both CRYs, and Casein-Kinase-1 present together incorporating its CLOCK-BMAL1 transcription factor target. Specifically, before incorporation, CLOCK-BMAL1 exists in a ~750-kDa complex. Through the use of single-particle electron microscopy, Weitz revealed purified mouse liver PER complexes to be somewhat spherical. PERs, CRYs and CK1 were separated into several small complexes, controlled by a pathway regulated by GAPDV1, a trafficking factor in the cytoplasm.

Awards and Achievements

 * 2018-2020: Dean's Innovation Award- Harvard Medical School
 * 2008-2017: G. Harold and Leila Y. Mather Charitable Foundation Award
 * 2007-2010: Neuroscience of Brain Disorders Award, McKnight Endowment Fund
 * 1994-1998: Scholar Award, McKnight Endowment Fund

Notable Publications

 * Aryal RA, Kwak PB, Tamayo AG, Gebert M, Chiu PL, Walz T, Weitz CJ. Macromolecular assemblies of the mammalian circadian clock. Mol. Cell 67, 770-782 (2017).
 * Ceriani F, Darlington TK, Staknis D, Mas P, Petti AA, Weitz CJ, Kay SA. Lightdependent sequestration of TIMELESS by CRYPTOCHROME. Science 285, 553-556 (1999)
 * Darlington TK, Wager-Smith K, Ceriani MF, Staknis D, Gekakis N, Steeves TDL, Weitz CJ, Takahashi JS, Kay SA. Closing the circadian loop: CLOCK induced transcription of its own inhibitors, period and timeless. Science 280, 1599-1603 (1998).
 * Duong HA, Robles MS, Knutti K, Weitz CJ. A molecular mechanism for circadian clock negative feedback. Science 332, 1436-1439 (2011).
 * Gekakis N, Saez L, Delahaye-Brown A-M, Myers MP, Sehgal A, Young MW, Weitz CJ. Isolation of timeless by PER protein interaction: Defective interaction of timeless protein with long-period mutant PERL. Science 270, 811-815 (1995)
 * Griffin EA, Staknis D, Weitz CJ. Light-independent role for CRY1 and CRY2 in the mammalian circadian clock. Science 286, 768-671 (1999).
 * Kramer A, Yang F-C, Snodgrass P, Li X, Scammell TE, Davis FC, Weitz CJ. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294, 2511-2515 (2001).
 * Lande-Diner L, Boyault C, Kim JY, Weitz, CJ. A positive feedback loop links circadian clock factor CLOCK-BMAL1 to the basic transcriptional machinery. Proc. Natl. Acad. Sci. USA 110, 16021-16026 (2013).
 * 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).
 * Sadacca LA, Lamia KA, Delemos AS, Blum B, Weitz CJ. An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia 54,120-124 (2011).
 * Sangoram AM, Saez L, Antoch MP, Gekakis N, Staknis D, Whitely A, Freuchte EM, Vitaterna MH, Shimomura K, King DP, Young, MW, Weitz CJ, Takahashi, JS. Mammalian circadian autoregulatory loop: a Timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron 21, 1101-1113 (1998).
 * Tamayo AG, Duong HA, Robles MS, Mann M, Weitz CJ. Histone mono-ubiquitination by a Clock–Bmal1 complex marks Per1 and Per2 genes for circadian feedback. Nature Struct. Mol. Biol. 22, 759-766 (2015).
 * Zhao W-N, Malinin N, Yang F-C, Staknis, D Gekakis N, Maier B, Reischl S, Kramer A, Weitz. CJ. CIPC is a mammalian circadian clock protein without invertebrate homologs. Nature Cell Biol. 3, 268-275 (2007).