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Charles Weitz

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Charles J. Weitz
EducationHarvard University
(BA)
Stanford University School of Medicine
(MD, PhD)
Johns Hopkins School of Medicine
(Post-Doc)
Known forCircadian rhythms
Scientific career
FieldsChronobiology
Neurobiology
Molecular Biology
InstitutionsHarvard Medical School

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. The Weitz lab is also accredited for discovering direct transcription termination by the PER complex, which regulates the expression of genes involved in producing the circadian rhythm.

Currently, Weitz's work focuses on using cryo-electron microscopy to study endogenous circadian protein complexes.

Education and academic career

Education

Charles J. Weitz earned his undergraduate degree in Philosophy from Harvard University in 1978.[1]

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 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. [2]

Academic career

Weitz went into teaching and was an assistant professor in the Department of Neurobiology at Harvard Medical School from 1993 to 1998, and associate professor in the Department of Neurobiology at Harvard Medical School from 1998 to 2003. He is currently the Robert Henry Pfeiffer Professor of Neurobiology at Harvard Medical School.[3]

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 and colleagues first identified dCLOCK, the Drosophila homolog of the mouse CLOCK protein. After this step, they were able to determine the protein product of dCLOCK could activate per and tim transcription. Through an E-box located on the promoters of per and tim, the proteins dCLOCK and BMAL1 are able to induce the expression of per and tim. Eventually, the protein products PERIOD and TIMELESS accumulate inside the nucleus. It is there where they inhibit the transcription activity of CLOCK at their promoters, thus forming a negative feedback loop.[4]

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.[5]

Discovery of feedback regulation by the PERIOD complex

Circadian rhythms are regulated by a transcriptional negative feedback loop. 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.[6]

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.[7] During the negative feedback loop, RNA polymerase II accumulates near termination sites on PER and CRY genes, promoting transcription of the genes.[7] As the PER complex is produced, the SETX interacts with the accumulated RNA polymerase II, blocking its release and inhibiting further transcription of the PER and CRY genes.[7] This discovery solidified insight into how PER proteins may repress clock-controlled target genes directly, contributing to future studies of the circadian clock's transcriptional architecture.[6]

Application of cryo-electron microscopy towards understanding the mammalian circadian clock

Cryo-electron microscopy (cryo-EM) is a cutting-edge technique that determines the three-dimensional structure of large molecules at high resolution.[8] 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.[8]

In 2017, Weitz, alongside Rajindra Aryal, Pieter Bas Kwak, Alfred Tamayo and Michael Gebert, applied this technique to enrich the understanding of the mammalian circadian clock. They deciphered macromolecular compositions of the circadian feedback loop, as well as internal structural properties of the clock’s function.[9] It was discovered that the PER complexes exhibited quasi-spherical structures, featuring globular domains that were connected by flexible linkers.[9] In the cytoplasm, GAPVD1, a cytoplasmic trafficking factor, regulates a system of complexes involved in producing a circadian rhythm.[9]

Circadian gene expression in the heart and liver

Role of CRY1 and CRY2 in circadian regulation

Selected Papers

  • Duong HA, Robles MS, Knutti K, Weitz CJ.  A molecular mechanism for circadian clock negative feedback. Science  332, 1436-1439 (2011)[10]
  • 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)[11]
  • Kim JY, Kwak PB, Weitz CJ. Specificity in circadian clock feedback from targeted reconstitution of the NuRD co-repressor.  Mol. Cell  56, 738-748 (2014)[12]
  • Aryal RA, Kwak PB, Tamayo AG, Chiu PL, Walz T, Weitz CJ.  Macromolecular assemblies of the mammalian circadian clock.  Mol. Cell  (2017, in press)[13]

References

  1. ^ Weitz, Charles (2023). "Charles Weitz Linkedin". Linkedin. Retrieved 11 April 2023.{{cite web}}: CS1 maint: url-status (link)
  2. ^ Weitz, C. J.; Went, L. N.; Nathans, J. (August 1992). "Human tritanopia associated with a third amino acid substitution in the blue-sensitive visual pigment". American Journal of Human Genetics. 51 (2): 444–446. ISSN 0002-9297. PMC 1682686. PMID 1386496.
  3. ^ "Charles Weitz". neuro.hms.harvard.edu. Retrieved 2023-04-11.
  4. ^ Darlington, Thomas K.; Wager-Smith, Karen; Ceriani, M. Fernanda; Staknis, David; Gekakis, Nicholas; Steeves, Thomas D. L.; Weitz, Charles J.; Takahashi, Joseph S.; Kay, Steve A. (1998-06-05). "Closing the Circadian Loop: CLOCK-Induced Transcription of Its Own Inhibitors per and tim". Science. 280 (5369): 1599–1603. doi:10.1126/science.280.5369.1599. ISSN 0036-8075.
  5. ^ Gekakis, Nicholas; Staknis, David; Nguyen, Hubert B.; Davis, Fred C.; Wilsbacher, Lisa D.; King, David P.; Takahashi, Joseph S.; Weitz, Charles J. (1998-06-05). "Role of the CLOCK Protein in the Mammalian Circadian Mechanism". Science. 280 (5369): 1564–1569. doi:10.1126/science.280.5369.1564. ISSN 0036-8075.
  6. ^ a b Partch, Carrie L.; Green, Carla B.; Takahashi, Joseph S. (2014-02-01). "Molecular architecture of the mammalian circadian clock". Trends in Cell Biology. 24 (2): 90–99. doi:10.1016/j.tcb.2013.07.002. ISSN 0962-8924. PMC 3946763. PMID 23916625.
  7. ^ a b c Padmanabhan, Kiran; Robles, Maria S.; Westerling, Thomas; Weitz, Charles J. (2012-08-03). "Feedback Regulation of Transcriptional Termination by the Mammalian Circadian Clock PERIOD Complex". Science. 337 (6094): 599–602. doi:10.1126/science.1221592. ISSN 0036-8075.
  8. ^ a b Callaway, Ewen (2020-02-10). "Revolutionary cryo-EM is taking over structural biology". Nature. 578 (7794): 201–201. doi:10.1038/d41586-020-00341-9.
  9. ^ a b c Aryal, Rajindra P.; Kwak, Pieter Bas; Tamayo, Alfred G.; Gebert, Michael; Chiu, Po-Lin; Walz, Thomas; Weitz, Charles J. (2017-09-07). "Macromolecular Assemblies of the Mammalian Circadian Clock". Molecular Cell. 67 (5): 770–782.e6. doi:10.1016/j.molcel.2017.07.017. ISSN 1097-2765. PMC 5679067. PMID 28886335.
  10. ^ Duong, H. A.; Robles, M. S.; Knutti, D.; Weitz, C. J. (2011-06-17). "A Molecular Mechanism for Circadian Clock Negative Feedback". Science. 332 (6036): 1436–1439. doi:10.1126/science.1196766. ISSN 0036-8075. PMC 3859310. PMID 21680841.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ Padmanabhan, Kiran; Robles, Maria S.; Westerling, Thomas; Weitz, Charles J. (2012-08-03). "Feedback Regulation of Transcriptional Termination by the Mammalian Circadian Clock PERIOD Complex". Science. 337 (6094): 599–602. doi:10.1126/science.1221592. ISSN 0036-8075.
  12. ^ Kim, Jin Young; Kwak, Pieter Bas; Weitz, Charles J. (2014-12). "Specificity in Circadian Clock Feedback from Targeted Reconstitution of the NuRD Corepressor". Molecular Cell. 56 (6): 738–748. doi:10.1016/j.molcel.2014.10.017. ISSN 1097-2765. {{cite journal}}: Check date values in: |date= (help); no-break space character in |first2= at position 7 (help); no-break space character in |first3= at position 8 (help); no-break space character in |first= at position 4 (help)
  13. ^ Aryal, Rajindra P.; Kwak, Pieter Bas; Tamayo, Alfred G.; Gebert, Michael; Chiu, Po-Lin; Walz, Thomas; Weitz, Charles J. (2017-09). "Macromolecular Assemblies of the Mammalian Circadian Clock". Molecular Cell. 67 (5): 770–782.e6. doi:10.1016/j.molcel.2017.07.017. {{cite journal}}: Check date values in: |date= (help)

Positions and honors

  1. ^ Cite error: The named reference Charles Weitz was invoked but never defined (see the help page).
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