John B. Hogenesch

Last updated
John B. Hogenesch
Born (1967-05-29) May 29, 1967 (age 57)
Rotterdam, Netherlands
CitizenshipAmerican
Alma mater
Scientific career
Fields Bioinformatics, genomics, chronobiology, computational biology
Institutions Cincinnati Children's Hospital Medical Center
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 Pediatrics at the Cincinnati Children's Hospital Medical Center. 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 currently the Deputy Director of the Center for Chronobiology, an Ohio Eminent Scholar, and Professor of Pediatrics in the Divisions of Perinatal Biology and Immunobiology at the Cincinnati Children's Hospital Medical Center.

Contents

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. [1] His parents both work at the University of Southern California. His father is a polymer chemist, [2] and his mother is a clinical instructor in psychiatry and behavioral sciences. [3] [4] His brother, Tom Hogen-Esch is a Political Science and Urban Studies professor at Cal State Northridge. [5] [6] John is married to his longtime partner Kelly Schilling, and they reside in the Cincinnati area.

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. [6] 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. [7] 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. [8] 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. [6]

Career

Discovery 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. [9] These transcription factors were initially named MOP1-5. [10] 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. [11] Later work revealed that Bmal1 is the only clock gene without which the circadian clock fails to function in humans. [12]

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. [11]

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. [13]

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. [14] [15] 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. [16]

Hogenesch became the Program Manager of Genomics at GNF in 2000, and remained there until 2004. [16] 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. [9] [17] These highly cited works, together cited over 3700 times, have been influential in the field of genome biology. [9] [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 colleagues 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 become a professor and the Director of Genome Technology at The Scripps Research Institute's other location in West Palm Beach, FL, where he continued his work on transcriptomes. [10] 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, NF-κB 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. [6]

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. [38] Further research has focused on the timing of drug administration with the goal of optimizing drug efficacy by allowing physicians to prescribe medicine to be taken when it is most effective and least likely to cause side effects. [39] [19] [40]

Related Research Articles

Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules. Other functional regions of the non-coding DNA fraction include regulatory sequences that control gene expression; scaffold attachment regions; origins of DNA replication; centromeres; and telomeres. Some non-coding regions appear to be mostly nonfunctional, such as introns, pseudogenes, intergenic DNA, and fragments of transposons and viruses. Regions that are completely nonfunctional are called junk DNA.

A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

<span class="mw-page-title-main">Cryptochrome</span> Class of photoreceptors in plants and animals

Cryptochromes are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the chromatic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

An E-box is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG, with a palindromic canonical sequence of CACGTG, is recognized and bound by transcription factors to initiate gene transcription. Once the transcription factors bind to the promoters through the E-box, other enzymes can bind to the promoter and facilitate transcription from DNA to mRNA.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">NPAS2</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

<span class="mw-page-title-main">Rev-ErbA alpha</span> Protein-coding gene in the species Homo sapiens

Rev-Erb alpha (Rev-Erbɑ), also known as nuclear receptor subfamily 1 group D member 1 (NR1D1), is one of two Rev-Erb proteins in the nuclear receptor (NR) family of intracellular transcription factors. In humans, REV-ERBɑ is encoded by the NR1D1 gene, which is highly conserved across animal species.

<span class="mw-page-title-main">ARNTL2</span> Protein-coding gene in humans

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.

<span class="mw-page-title-main">RAR-related orphan receptor alpha</span> Protein-coding gene in the species Homo sapiens

RAR-related orphan receptor alpha (RORα), also known as NR1F1 is a nuclear receptor that in humans is encoded by the RORA gene. RORα participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, RORα is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.

<span class="mw-page-title-main">RAR-related orphan receptor gamma</span> Cellular receptor

RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC gene. RORγ is a member of the nuclear receptor family of transcription factors. It is mainly expressed in immune cells and it also regulates circadian rhythms. It may be involved in the progression of certain types of cancer.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Human protein and coding gene

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

<i>Cycle</i> (gene)

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix–loop–helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include basic helix-loop-helix ARNT-like protein 1 (ARNTL) and Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2).

<span class="mw-page-title-main">Michael Rosbash</span> American geneticist and chronobiologist (born 1944)

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".

Steve A. Kay is a British-born chronobiologist who mainly works in the United States. Dr. Kay has pioneered methods to monitor daily gene expression in real time and characterized circadian gene expression in plants, flies and mammals. In 2014, Steve Kay celebrated 25 years of successful chronobiology research at the Kaylab 25 Symposium, joined by over one hundred researchers with whom he had collaborated with or mentored. Dr. Kay, a member of the National Academy of Sciences, U.S.A., briefly served as president of The Scripps Research Institute. and is currently a professor at the University of Southern California. He also served on the Life Sciences jury for the Infosys Prize in 2011.

Paul Hardin is an American scientist in the field of chronobiology and a pioneering researcher in the understanding of circadian clocks in flies and mammals. Hardin currently serves as a distinguished professor in the biology department at Texas A&M University. He is best known for his discovery of circadian oscillations in the mRNA of the clock gene Period (per), the importance of the E-Box in per activation, the interlocked feedback loops that control rhythms in activator gene transcription, and the circadian regulation of olfaction in Drosophila melanogaster. Born in a suburb of Chicago, Matteson, Illinois, Hardin currently resides in College Station, Texas, with his wife and three children.

Jay Dunlap is an American chronobiologist and photobiologist who has made significant contributions to the field of chronobiology by investigating the underlying mechanisms of circadian systems in Neurospora, a fungus commonly used as a model organism in biology, and in mice and mammalian cell culture models. Major contributions by Jay Dunlap include his work investigating the role of frq and wc clock genes in circadian rhythmicity, and his leadership in coordinating the whole genome knockout collection for Neurospora. He is currently the Nathan Smith Professor of Molecular and Systems Biology at the Geisel School of Medicine at Dartmouth. He and his colleague Jennifer Loros have mentored numerous students and postdoctoral fellows, many of whom presently hold positions at various academic institutions.

Carla Beth Green is an American neurobiologist and chronobiologist. She is a professor in the Department of Neuroscience and a Distinguished Scholar in Neuroscience at the University of Texas Southwestern Medical Center. She is the former president of the Society for Research on Biological Rhythms (SRBR), as well as a satellite member of the International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan.

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

References

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