John B. Hogenesch

John B. Hogenesch
Born (1967-05-29) May 29, 1967
Rotterdam, Netherlands
Citizenship American
Fields Bioinformatics, genomics, chronobiology, computational biology
Institutions Perelman School of Medicine
Alma mater
Thesis Characterization of basic-helix-loop-helix-PER-ARNT-SIM-mediated signaling pathways (1999)
Doctoral advisor Chris Bradfield
Website
http://hogeneschlab.org/

John B. Hogenesch (born May 29, 1967) is an American chronobiologist and Professor of Pharmacology at the University of Pennsylvania.[1] The primary focus of his work has been studying the network of mammalian clock genes from the genomic and computational perspective to further the understanding of circadian behavior. He is now Professor and Vice Chair of Systems Pharmacology and Translational Therapeutics and Interim Director of the Institute for Biomedical Informatics for the Perelman School of Medicine as well as Associate Director of the Penn Genome Frontiers Institute.[2]

Personal life

Family

Hogenesch was born on May 29, 1967, in Rotterdam, Netherlands. He was raised in Gainesville, Florida, by his father Thieo E. Hogen-Esch and his mother Cheryl H. St. George.[3] His parents both work at the University of Southern California. His father is a polymer chemist,[4] and his mother is a clinical instructor in psychiatry and behavioral sciences.[5][6] His brother, Tom Hogen-Esch is a Political Science and Urban Studies professor at Cal State Northridge.[7][8]

Education

Hogenesch originally received a B.A. in History from the University of Southern California in 1989 followed by a B.S. in Biology in 1991. He was inspired to study chronobiology by Joseph Takahashi in the fall of 1992 after learning about the Drosophila clock in a lecture.[8] In 1999 Hogenesch completed a Ph.D. in Neuroscience at Northwestern University's Chicago campus, studying transcription factors with basic helix-loop-helix (BHLH) and PAS protein domains.[1] Hogenesh was mentored by Chris Bradfield, now a professor of oncology and the Director of the Molecular and Environmental Toxicology Graduate Program at the University of Wisconsin-Madison.[9] He continued his research on functional genomics as a postdoctoral researcher with Dr. Steve A. Kay at the Genomics Institute of the Novartis Research Foundation.[8]

Career

Discovering of Bmal1

In March, 1997, Hogenesch was a neuroscience graduate student at Northwestern University in the laboratory of Christopher Bradfield, when he discovered five transcription factors in the basic helix-loop-helix-PAS (bHLH-PAS) domain superfamily during his thesis work.[10] These transcription factors were initially named MOP1-5.[11] Hogenesch’s later characterization of MOP3, better known as BMAL1 or ARNTL, revealed in 1998 that its role as a partner of the bHLH-PAS transcription factor CLOCK was essential to the function of the mammalian circadian clock. BMAL1 and CLOCK are now the two most well recognized bHLH-PAS domain transcription factors.[12] Later work revealed that BMAL1 is the only clock gene without which the circadian clock fails to function in humans.[13]

BMAL1 functions as a positive element in the circadian clock. It forms a heterodimer with CLOCK to initiate transcription of target genes that contain E-box sequences, such as Period and Cryptochrome in mice. The BMAL1:CLOCK complex is suppressed by the buildup of the PER:CRY heterodimers.[12]

After receiving his Ph.D. in 1999, Hogenesch followed his Ph.D. mentor Christopher Bradfield to the University of Wisconsin-Madison and continued in his lab as a postdoctoral associate. During this time, Hogenesch focused on following up on his Ph.D. work.[14]

Assembling & mRNA characterization of complete mammalian transcriptomes

Later in 1999, he became a postdoctoral associate with Steve A. Kay and Peter G. Schultz. Kay was employed by the University of California at San Diego and the Scripps Research Institute, while Schultz was employed at the Scripps Research Institute and was founder and director of The Genomics Institute of the Novartis Research Foundation (GNF) in La Jolla, CA.[15][16] Hogenesch started work on the human transcriptome and the mRNA characterization of the transcriptomes of humans, mice, and rats, which he would later continue as Director of Genomics at GNF.[17]

Hogenesch became the Program Manager of Genomics at GNF in 2000, and remained there until 2004.[17] During his time there, he accomplished the compilation of the complete human transcriptome, and also the mRNA characterization of the human, mouse, and rat transcriptomes.[10][18] These highly cited works, together cited over 3700 times, have been influential in the field of genome biology.[10][18] Hogenesch then brought together his work on the human and mouse transcriptomes into a gene atlas, which he made available as a tool for other genome biologists.[19]

Characterizing circadian regulation of transcription

In addition to characterizing transciptomes present in various organisms, Hogenesch has also spent time throughout his career determining which genes were regulated on a circadian schedule. Working with his colleges he has determined that mRNA in plants,[20] flies,[21] mice,[22] and humans[23] all shows extensive circadian regulation. In mammals up to 43% of all genes are regulated according to a circadian clock.[24] Transcription for circadianly regulated mRNA shows regular peaks in morning and evening,[25] which then has implications for the regulation of drug targets.[26]

Non-coding RNA and functional genomics

In 2004 Hogenesch left California to became a professor and the Director of Genome Technology at The Scripps Research Institute's other location in West Palm Beach, FL, where he continues his work on transcriptomes.[11] Hogenesch contributed to a study published in 2005 which used new RNAi genetic screening techniques to discover a non-coding RNA (ncRNA) known as NRON. NRON, a repressor of the protein NFAT, is one of the first well characterized examples of a ncRNAs involved in transcription regulation.[27][28][29]

In 2006, Hogenesch moved to the Perelman School of Medicine at the University of Pennsylvania where he continues to study mammalian circadian clocks and genome function. One of his current research directions includes incorporating research on noncoding RNA, such as siRNA or hairpin RNA isolated by combining forward genetics and genomic screens.[18] He has used this technique on miRNA to examine signalling and cell survival.[30]

Contributions to the core clock mechanisms and the field of chronobiology

Over the course of his career, Hogenesch has made numerous contributions to the understanding of the core clock mechanisms. He discovered the key proteins Bmal1 (Arntl), and Bmal2 early in his career. He was also on the team that discovered Rora to be an important regulator of Bmal1.[31] Rora is currently under investigation for a possible connection to autism, which may relate to its function as a circadian regulator.[32] Hogenesch has also contributed to the identification of hundreds more genes that modulate circadian rhythms in humans by using genome wide RNAi scanning.[33] More recently, he discovered new clock gene CHRONO using novel computer based machine learning techniques to prioritize clock gene candidates.[34][35]

Hogenesch has also contributed to the field by mentored scientists like Satchin Panda[36] and has collaborated with over 25 other scientists on a variety of papers that cover a range of topics including CREB signaling, NFkB signaling, TRP channels, melanopsin signaling, cell type specific splicing, noncoding RNA function, and RNA-seq methods and mapping algorithms.[37]

Applications of scientific achievements

Wikipedia and chronobiology

Hogenesh has pushed for the chronobiology community to create Wikipedia pages about genes through a project called Gene Wiki. The result has been the creation of pages about genes involved in the circadian clock such as ARNTL, as well as pages about chronobiologists like Ingeborg Beling.[8]

He has also been instrumental in creating the Gene Atlas. This project uses a database run by Hogenesch called the Circa database that lists time of activity of genes in different tissues.[24] As an open source database, it allows biologists and pharmaceutical researchers to determine the peak time of different genes and mRNA which can then be used to target drug treatments.

Medicinal uses of chronobiology

In October 2014, Hogenesch's discovery that many proteins targeted by drugs experience circadian fluctuations made strides towards chronotherapy treatment. A future focus on the timing of drug administration will optimize drug efficacy by allowing physicians prescribe medicine to be taken when it is most effective.[19][38]

References

  1. 1 2 The Trustees of the University of Pennsylvania (January 22, 2015), John B. Hogenesch, Ph.D., retrieved April 8, 2015
  2. ↑ The Trustees of the University of Pennsylvania, ITMAT Internal Advisory Board, retrieved April 8, 2015
  3. ↑ Singer, Glenn (March 6, 2005). "Assembling The Team". Sun Sentinel. Retrieved April 9, 2015.
  4. ↑ Chemistry Dept., USC College of Letters, Arts & Sciences, Thieo E. Hogen-Esch, retrieved April 8, 2015
  5. ↑ University of Southern California Directory, Cheryl H. St. George, retrieved April 22, 2015
  6. ↑ The Gator Nurse (2013), Honor Role 2013, retrieved April 22, 2015
  7. ↑ California State University, Northridge, Tom Hogen-Esch, retrieved April 8, 2015
  8. 1 2 3 4 Coturnix (August 13, 2009), Clock Interview: John Hogenesch, ScienceBlogs, retrieved April 8, 2015
  9. ↑ The Board of Regents of the University of Wisconsin System (April 8, 2015), Christopher A. Bradfield, PhD, retrieved April 8, 2015
  10. 1 2 3 NIMH Silvo O. Conte Center for Neuroscience Research (2006), Dr. John Hogenesch, retrieved April 8, 2015
  11. 1 2 John Hogenesch, Coursera Inc, 2015, retrieved April 8, 2015
  12. 1 2 Ko, C. H.; Takahashi, Joseph S. (2006). "Molecular Components Of The Mammalian Circadian Clock". Human Molecular Genetics 15 (2): R271–7. doi:10.1093/hmg/ddl207. PMID 16987893.
  13. ↑ Reppert, Steven M.; Weaver, David R. (August 2002). "Coordination of circadian timing in mammals". Nature 418: 935–941. doi:10.1038/nature00965. PMID 12198538.
  14. ↑ University of Wisconsin-Madison - Office of the Provost (2013), Christopher A. Bradfield, Ph.D. Curriculum Vitae (PDF), University of Wisconsin-Madison, retrieved April 8, 2015
  15. ↑ The Scripps Research Institute - La Jolla (2014), Peter G. Schultz, The Scripps Research Institute, retrieved April 9, 2015
  16. ↑ USC Dornsife (2015), Steve A. Kay Ph.D., USC Dornsife, retrieved April 9, 2015
  17. 1 2 The Scripps Research Institute - Florida (2004). "Scientific Report 2004 for Scripps Florida" (PDF). Scientific Report 1: 11.
  18. 1 2 3 RIKEN Center for Developmental Biology (2006), Speaker Profiles: John Hoganesh, RIKEN Center for Developmental Biology, retrieved April 9, 2015
  19. 1 2 Amanda Schaffer (2014), An Atlas of Genetic Time, The New Yorker, retrieved April 9, 2015
  20. ↑ Winkel-Shirley, Brenda (June 2001). "Flavonoid Biosynthesis. A Colorful Model for Genetics, Biochemistry, Cell Biology, and Biotechnology". Plant Physiology 126: 485–493. doi:10.1104/pp.126.2.485. PMC 1540115. PMID 11402179. Retrieved April 23, 2015.
  21. ↑ Wijnen, Herman; Young, Michael W. (2006). "Interplay of Circadian Clocks and Metabolic Rhythms". Annual Review of Genetics 40: 409–448. doi:10.1146/annurev.genet.40.110405.090603.
  22. ↑ Lein, Ed S.; Hawrylycz, Michael J.; Ao, Nancy (November 15, 2006). "Genome-wide atlas of gene expression in the adult mouse brain". Nature 445 (445): 168–176. doi:10.1038/nature05453. PMID 17151600. Retrieved April 23, 2015.
  23. ↑ Dibner, Charna; Schibler, Ueli; Albrecht, Urs (2010). "The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks" (PDF). Annual Review of Physiology 72: 517–549. doi:10.1146/annurev-physiol-021909-135821. PMID 20148687. Retrieved April 23, 2015.
  24. 1 2 Schaffer, Amanda (November 21, 2014). "An Atlas of Genetic Time". The New Yorker. Retrieved April 23, 2015.
  25. ↑ Grima, Brigitte; Chélot, Elisabeth; Xia, Ruohan; Rouyer, François (October 14, 2004). "Morning and evening peaks of activity rely on different clock neurons of the Drosophila brain". Nature 431: 869–873. doi:10.1038/nature02935. PMID 15483616. Retrieved April 23, 2015.
  26. ↑ Grundschober, Christophe (October 11, 2001). "Circadian Regulation of Diverse Gene Products Revealed by mRNA Expression Profiling of Synchronized Fibroblasts". The Journal of Biological Chemistry 276: 46751–46758. doi:10.1074/jbc.M107499200. Retrieved April 23, 2015.
  27. ↑ Willingham, A. T., A. P. Orth, S. Batalov, E. C. Peters, B. G. Wen, P. Aza-Blanc, J. B. Hogenesch, and P. G. Schltz. (2005). "A Strategy for Probing the Function of Noncoding RNAs Finds a Repressor of NFAT". Science 309 (5740): 1570–1573. doi:10.1126/science.1115901. PMID 16141075. Retrieved April 23, 2015.
  28. ↑ Wilusz, J. E., H. Sunwoo, and D. L. Spector. (2009). "Long noncoding RNAs: functional surprises from the RNA world". Genes & Development 23: 1494–1504. doi:10.1101/gad.1800909. Retrieved April 23, 2015.
  29. ↑ Prasanth, K. V. and D. L. Spector (2007). "Eukaryotic regulatory RNAs: an answer to the ‘genome complexity’ conundrum". Genes & Development 21: 11–42. doi:10.1101/gad.1484207. Retrieved April 23, 2015.
  30. ↑ Haemming, S (June 5, 2014). "miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas". Nature 5: e1279. doi:10.1038/cddis.2014.245. Retrieved April 23, 2015.
  31. ↑ Trey K. Sato, Satchidananda Panda, Loren J. Miraglia, Teresa M. Reyes, Radu D. Rudic, Peter McNamara, Kinnery A. Naik, Garret A. FitzGerald, Steve A. Kay, John B. Hogenesch. (2004). "A Functional Genomics Strategy Reveals Rora as a Component of the Mammalian Circadian Clock.". Neuron 43 (4): 527–537. doi:10.1016/j.neuron.2004.07.018. PMID 15312651. Retrieved April 23, 2015.
  32. ↑ Virginia Hughes (2013), Study uncovers molecular targets of autism-linked RORA gene, Simmons Foundation Autism Research Initiative, retrieved April 23, 2015
  33. ↑ Eric E. Zhang, Andrew C. Liu, Tsuyoshi Hirota, Loren J. Miraglia, Genevieve Welch, Pagkapol Y. Pongsawakul, Xianzhong Liu, Ann Atwood, Jon W. Huss III, Jeff Janes, Andrew I. Su, John B. Hogenesch, Steve A. Kay. (October 2, 2009). "A Genome-wide RNAi Screen for Modifiers of the Circadian Clock in Human Cells". Cell 139 (1): 199–210. doi:10.1016/j.cell.2009.08.031. PMC 2777987. PMID 19765810. Retrieved April 23, 2015.
  34. ↑ Ron C. Anafi, Yool Lee, Trey K. Sato, Anand Venkataraman, Chidambaram Ramanathan, Ibrahim H. Kavakli, Michael E. Hughes, Julie E. Baggs, Jacqueline Growe, Andrew C. Liu, Junhyong Kim, John B. Hogenesch. (April 15, 2014). "Machine Learning Helps Identify CHRONO as a Circadian Clock Component". PLoS Biology 12 (4): e1001840. doi:10.1371/journal.pbio.1001840. doi:10.1371/journal.pbio.1001840. Retrieved April 23, 2015.
  35. ↑ Scientists Unwind a Circadian Clock Mystery, Genetic Engineering and Biotechnology News, April 16, 2014, retrieved April 23, 2015
  36. ↑ "Hogenesch Lab: Members". Hogenesch Lab. 2015. Retrieved April 18, 2015.
  37. ↑ "Co-authors for John B. Hogenesch". Google. Retrieved April 9, 2015.
  38. ↑ Ray Zhang, Nicholas F. Lahens, and Heather I. Ballance (2014), First Atlas of Body Clock Gene Expression in Mammals Informs Timing of Drug Delivery and Emerging Field of Chronotherapy: Penn Medicine study has implications for 100 top-selling US drugs, half of which target daily-oscillating genes, Penn Medicine, retrieved April 9, 2015

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