Jeannie T. Lee

Last updated
Jeannie T. Lee
Alma materHarvard University, University of Pennsylvania Medical School, Massachusetts Institute of Technology
Awards2018 Harrington Rare Genetic Disease Scholar

2016 Lurie Award 2016 Centennial Award from Genetics Society of America 2015 Election to National Academy of Sciences (NAS) 2010 Molecular Biology Award from NAS 1999 Pew Scholar

1998 Basil O'Connor Scholar

Contents

Scientific career
Fieldsepigenetics, long noncoding RNA, X-inactivation, 3D genome, X-chromosome reactivation technology
Thesis  (1993)
Academic advisors Nancy Kleckner, Robert Nussbaum, Rudolf Jaenisch

Jeannie T. Lee is a Professor of Genetics (and Pathology) at Harvard Medical School and the Massachusetts General Hospital, and a Howard Hughes Medical Institute Investigator. She is known for her work on X-chromosome inactivation and for discovering the functions of a new class of epigenetic regulators known as long noncoding RNAs (lncRNAs), including Xist and Tsix.

Education

Jeannie T. Lee received an AB from Harvard College in Biochemistry & Molecular Biology and an MD/PhD in 1993 [1] from the University of Pennsylvania School of Medicine. [2] While at Harvard she worked with Nancy Kleckner on antisense regulation of Tn10 transposition. While at University of Pennsylvania School of Medicine her advisor was Robert L. Nussbaum. [3] Her PhD research focused on Fragile X syndrome, and led to her strong interest in X chromosome inactivation and epigenetics. [4] Then she did postdoctoral work with Rudolf Jaenisch at the Whitehead Institute , during which she discovered the nature of the X-inactivation center. [3] She was also Chief Resident of Laboratory Medicine at the Massachusetts General Hospital.

Research career

Lee joined the faculty at Harvard in 1997 and devoted her studies to noncoding RNA and sex chromosome dynamics during development and disease. Her major career research achievements include identifying the X inactivation center, [5] [6] discovering Tsix antisense RNA, [7] determining Xist's mechanism of action, [8] [9] demonstrating that a lncRNA is a regulator of Polycomb repressive complex 2, [8] [10] [11] [12] and determining that the X chromosome folds like origami and adopts a unique conformation.

Her studies established the existence and function of a group of lncRNAs. In a 2013 interview, she stated that this group of RNAs excited her because they control gene expression in a locus-specific way, by recruiting chromatin modifying activities to the locus, making the lncRNAs excellent drug design targets. She founded RaNA Therapeutics to test this idea. [3]

Upon conferring the Lurie Prize to Lee in 2016, Dr. Charles A. Sanders of the Foundation for the National Institutes of Health remarked: “Dr. Lee’s work has revolutionized the field of epigenetics. Her research has led to groundbreaking contributions, and we now have a better understanding of the unique role that long non-coding RNAs play in gene expression, which could lead to the development of new therapeutics.” [13]

Lee was President of the Genetics Society of America, [14] Codirector of the Harvard Epigenetics Initiative, and is Vice Chair of the Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School. She delivered a set of lectures to iBiology on X chromosome inactivation. [15]

Notable publications

Awards

Related Research Articles

<span class="mw-page-title-main">Barr body</span> Form taken by the inactive X chromosome in a female somatic cell

A Barr body or X-chromatin is an inactive X chromosome. In species with XY sex-determination, females typically have two X chromosomes, and one is rendered inactive in a process called lyonization. Errors in chromosome separation can also result in male and female individuals with extra X chromosomes. The Lyon hypothesis states that in cells with multiple X chromosomes, all but one are inactivated early in embryonic development in mammals. The X chromosomes that become inactivated are chosen randomly, except in marsupials and in some extra-embryonic tissues of some placental mammals, in which the X chromosome from the sperm is always deactivated.

<span class="mw-page-title-main">Peptide nucleic acid</span> Biological molecule

Peptide nucleic acid (PNA) is an artificially synthesized polymer similar to DNA or RNA.

<span class="mw-page-title-main">Non-coding RNA</span> Class of ribonucleic acid that is not translated into proteins

A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-coding RNAs include transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), as well as small RNAs such as microRNAs, siRNAs, piRNAs, snoRNAs, snRNAs, exRNAs, scaRNAs and the long ncRNAs such as Xist and HOTAIR.

<span class="mw-page-title-main">Antisense RNA</span>

Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks its translation into protein. The asRNAs have been found in both prokaryotes and eukaryotes, and can be classified into short and long non-coding RNAs (ncRNAs). The primary function of asRNA is regulating gene expression. asRNAs may also be produced synthetically and have found wide spread use as research tools for gene knockdown. They may also have therapeutic applications.

<span class="mw-page-title-main">Sex-chromosome dosage compensation</span>

Dosage compensation is the process by which organisms equalize the expression of genes between members of different biological sexes. Across species, different sexes are often characterized by different types and numbers of sex chromosomes. In order to neutralize the large difference in gene dosage produced by differing numbers of sex chromosomes among the sexes, various evolutionary branches have acquired various methods to equalize gene expression among the sexes. Because sex chromosomes contain different numbers of genes, different species of organisms have developed different mechanisms to cope with this inequality. Replicating the actual gene is impossible; thus organisms instead equalize the expression from each gene. For example, in humans, female (XX) cells randomly silence the transcription of one X chromosome, and transcribe all information from the other, expressed X chromosome. Thus, human females have the same number of expressed X-linked genes per cell as do human males (XY), both sexes having essentially one X chromosome per cell, from which to transcribe and express genes.

<span class="mw-page-title-main">X-inactivation</span> Inactivation of copies of X chromosome

X-inactivation is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome.

Polycomb-group proteins are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes through modulation of chromatin structure during embryonic development in fruit flies. They derive their name from the fact that the first sign of a decrease in PcG function is often a homeotic transformation of posterior legs towards anterior legs, which have a characteristic comb-like set of bristles.

<span class="mw-page-title-main">KCNQ1OT1</span>

KCNQ1 overlapping transcript 1, also known as KCNQ1OT1, is a long non-coding RNA gene found in the KCNQ1 locus. This locus consists of 8–10 protein-coding genes, specifically expressed from the maternal allele, and the paternally expressed non-coding RNA gene KCNQ1OT1. KCNQ1OT1 and KCNQ1 are imprinted genes and are part of an imprinting control region (ICR). Mitsuya identified that KCNQ1OT1 is an antisense transcript of KCNQ1. KCNQ1OT1 is a paternally expressed allele and KCNQ1 is a maternally expressed allele. KCNQ1OT1 is a nuclear, 91 kb transcript, found in close proximity to the nucleolus in certain cell types.

<span class="mw-page-title-main">XIST</span> Non-coding RNA

Xist is a non-coding RNA transcribed from the X chromosome of the placental mammals that acts as a major effector of the X-inactivation process. It is a component of the Xic – X-chromosome inactivation centre – along with two other RNA genes and two protein genes.

<span class="mw-page-title-main">Long non-coding RNA</span> Non-protein coding transcripts longer than 200 nucleotides

Long non-coding RNAs are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. Given that some lncRNAs have been reported to have the potential to encode small proteins or micro-peptides, the latest definition of lncRNA is a class of RNA molecules of over 200 nucleotides that have no or limited coding capacity. Long intervening/intergenic noncoding RNAs (lincRNAs) are sequences of lncRNA which do not overlap protein-coding genes.

<span class="mw-page-title-main">HOTAIR</span> Gene found in humans

HOTAIR is a human gene located between HOXC11 and HOXC12 on chromosome 12. It is the first example of an RNA expressed on one chromosome that has been found to influence transcription of HOXD cluster posterior genes located on chromosome 2. The sequence and function of HOTAIR is different in human and mouse. Sequence analysis of HOTAIR revealed that it exists in mammals, has poorly conserved sequences and considerably conserved structures, and has evolved faster than nearby HoxC genes. A subsequent study identified HOTAIR has 32 nucleotide long conserved noncoding element (CNE) that has a paralogous copy in HOXD cluster region, suggesting that the HOTAIR conserved sequences predates whole genome duplication events at the root of vertebrate. While the conserved sequence paralogous with HOXD cluster is 32 nucleotide long, the HOTAIR sequence conserved from human to fish is about 200 nucleotide long and is marked by active enhancer features.

<span class="mw-page-title-main">Jpx (gene)</span> Non-coding RNA in the species Homo sapiens

In molecular biology, JPX transcript, XIST activator, also known as Jpx, is a long non-coding RNA. In humans, it is located on the X chromosome. It was identified during sequence analysis of the X inactivation centre, surrounding the Xist gene. Jpx upregulates expression of Xist.

<span class="mw-page-title-main">HOXA11-AS1</span> Long non-coding RNA from the antisense strand in the homeobox A (HOXA gene).

HOXA11-AS lncRNA is a long non-coding RNA from the antisense strand in the homeobox A. The HOX gene contains four clusters. The sense strand of the HOXA gene codes for proteins. Alternative names for HOXA11-AS lncRNA are: HOXA-AS5, HOXA11S, HOXA11-AS1, HOXA11AS, or NCRNA00076. This gene is 3,885 nucleotides long and resides at chromosome 7 (7p15.2) and is transcribed from an independent gene promoter. Being a lncRNA, it is longer than 200 nucleotides in length, in contrast to regular non-coding RNAs.

<span class="mw-page-title-main">Tsix</span> Non-coding RNA in the species Homo sapiens

Tsix is a non-coding RNA gene that is antisense to the Xist RNA. Tsix binds Xist during X chromosome inactivation. The name Tsix comes from the reverse of Xist, which stands for X-inactive specific transcript.

Epigenetics of human development is the study of how epigenetics effects human development.

<span class="mw-page-title-main">Polycomb recruitment in X chromosome inactivation</span>

X chromosome inactivation (XCI) is the phenomenon that has been selected during the evolution to balance X-linked gene dosage between XX females and XY males.

<span class="mw-page-title-main">Neil Brockdorff</span> British biochemist (born 1958)

Neil Alexander Steven Brockdorff is a Wellcome Trust Principal Research Fellow and professor in the department of biochemistry at the University of Oxford. Brockdorff's research investigates gene and genome regulation in mammalian development. His interests are in the molecular basis of X-inactivation, the process that evolved in mammals to equalise X chromosome gene expression levels in XX females relative to XY males.

Carolyn J. Brown is a Canadian geneticist and Professor in the Department of Medical Genetics at the University of British Columbia. Brown is known for her studies on X-chromosome inactivation, having discovered the human XIST gene in 1990.

ncRNA therapy

A majority of the human genome is made up of non-protein coding DNA. It infers that such sequences are not commonly employed to encode for a protein. However, even though these regions do not code for protein, they have other functions and carry necessary regulatory information.They can be classified based on the size of the ncRNA. Small noncoding RNA is usually categorized as being under 200 bp in length, whereas long noncoding RNA is greater than 200bp. In addition, they can be categorized by their function within the cell; Infrastructural and Regulatory ncRNAs. Infrastructural ncRNAs seem to have a housekeeping role in translation and splicing and include species such as rRNA, tRNA, snRNA.Regulatory ncRNAs are involved in the modification of other RNAs.

X chromosome reactivation (XCR) is the process by which the inactive X chromosome (the Xi) is re-activated in the cells of eutherian female mammals. Therian female mammalian cells have two X chromosomes, while males have only one, requiring X-chromosome inactivation (XCI) for sex-chromosome dosage compensation. In eutherians, XCI is the random inactivation of one of the X chromosomes, silencing its expression. Much of the scientific knowledge currently known about XCR comes from research limited to mouse models or stem cells.

References

  1. ↑ "Jeannie T. Lee". Massachusetts General Hospital. Retrieved August 15, 2018.
  2. ↑ "Jeannie T. Lee".
  3. 1 2 3 "Interview with Jeannie T. Lee". Oligonucleotide Therapeutics Society. August 13, 2016.
  4. ↑ Viegas, J (2015). "QnAs with Jeannie T. Lee". Proc Natl Acad Sci U S A. 112 (48): 14745–6. Bibcode:2015PNAS..11214745V. doi: 10.1073/pnas.1521185112 . PMC   4672782 . PMID   26582793.
  5. ↑ Lee, J. T.; Strauss, W. M.; Dausman, J. A.; Jaenisch, R. (1996-07-12). "A 450 kb transgene displays properties of the mammalian X-inactivation center". Cell. 86 (1): 83–94. doi: 10.1016/s0092-8674(00)80079-3 . ISSN   0092-8674. PMID   8689690. S2CID   17888183.
  6. ↑ Lee, J. T.; Lu, N.; Han, Y. (1999-03-30). "Genetic analysis of the mouse X inactivation center defines an 80-kb multifunction domain". Proceedings of the National Academy of Sciences of the United States of America. 96 (7): 3836–3841. Bibcode:1999PNAS...96.3836L. doi: 10.1073/pnas.96.7.3836 . ISSN   0027-8424. PMC   22381 . PMID   10097124.
  7. 1 2 Lee, J. T.; Davidow, L. S.; Warshawsky, D. (April 1999). "Tsix, a gene antisense to Xist at the X-inactivation centre". Nature Genetics. 21 (4): 400–404. doi:10.1038/7734. ISSN   1061-4036. PMID   10192391. S2CID   30636065.
  8. 1 2 3 Zhao, Jing; Sun, Bryan K.; Erwin, Jennifer A.; Song, Ji-Joon; Lee, Jeannie T. (2008-10-31). "Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome". Science. 322 (5902): 750–756. Bibcode:2008Sci...322..750Z. doi:10.1126/science.1163045. ISSN   1095-9203. PMC   2748911 . PMID   18974356.
  9. ↑ Minajigi, Anand; Froberg, John; Wei, Chunyao; Sunwoo, Hongjae; Kesner, Barry; Colognori, David; Lessing, Derek; Payer, Bernhard; Boukhali, Myriam (2015-07-17). "A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation". Science. 349 (6245): aab2276. doi:10.1126/science.aab2276. ISSN   0036-8075. PMC   4845908 . PMID   26089354.
  10. ↑ Zhao, Jing; Ohsumi, Toshiro K.; Kung, Johnny T.; Ogawa, Yuya; Grau, Daniel J.; Sarma, Kavitha; Song, Ji Joon; Kingston, Robert E.; Borowsky, Mark (2010-12-22). "Genome-wide identification of polycomb-associated RNAs by RIP-seq". Molecular Cell. 40 (6): 939–953. doi:10.1016/j.molcel.2010.12.011. ISSN   1097-4164. PMC   3021903 . PMID   21172659.
  11. ↑ Cifuentes-Rojas, Catherine; Hernandez, Alfredo J.; Sarma, Kavitha; Lee, Jeannie T. (2014-07-17). "Regulatory interactions between RNA and polycomb repressive complex 2". Molecular Cell. 55 (2): 171–185. doi:10.1016/j.molcel.2014.05.009. ISSN   1097-4164. PMC   4107928 . PMID   24882207.
  12. ↑ Zovoilis, Athanasios; Cifuentes-Rojas, Catherine; Chu, Hsueh-Ping; Hernandez, Alfredo J.; Lee, Jeannie T. (2016-12-15). "Destabilization of B2 RNA by EZH2 Activates the Stress Response". Cell. 167 (7): 1788–1802.e13. doi:10.1016/j.cell.2016.11.041. ISSN   1097-4172. PMC   5552366 . PMID   27984727.
  13. ↑ "Foundation for the NIH to Award Lurie Prize in Biomedical Sciences to Dr. Jeannie Lee for Pioneering Work in Epigenetics | FNIH". fnih.org. Archived from the original on 2017-09-30. Retrieved 2017-09-30.
  14. 1 2 "Jeannie T. Lee".
  15. ↑ "Jeannie Lee • iBiology". iBiology. Retrieved 2019-12-15.
  16. ↑ Kung, Johnny T. Y.; Colognori, David; Lee, Jeannie T. (March 2013). "Long noncoding RNAs: past, present, and future". Genetics. 193 (3): 651–669. doi:10.1534/genetics.112.146704. ISSN   1943-2631. PMC   3583990 . PMID   23463798.
  17. ↑ Lee, Jeannie T. (2012-12-14). "Epigenetic regulation by long noncoding RNAs". Science. 338 (6113): 1435–1439. Bibcode:2012Sci...338.1435L. doi:10.1126/science.1231776. ISSN   1095-9203. PMID   23239728. S2CID   206546141.
  18. ↑ Zhao, Jing; Ohsumi, Toshiro K.; Kung, Johnny T.; Ogawa, Yuya; Grau, Daniel J.; Sarma, Kavitha; Song, Ji Joon; Kingston, Robert E.; Borowsky, Mark; Lee, Jeannie T. (2010-12-22). "Genome-wide identification of polycomb-associated RNAs by RIP-seq". Molecular Cell. 40 (6): 939–953. doi:10.1016/j.molcel.2010.12.011. ISSN   1097-4164. PMC   3021903 . PMID   21172659.
  19. ↑ Jeon, Yesu; Lee, Jeannie T. (2011-07-08). "YY1 tethers Xist RNA to the inactive X nucleation center". Cell. 146 (1): 119–133. doi:10.1016/j.cell.2011.06.026. ISSN   1097-4172. PMC   3150513 . PMID   21729784.
  20. ↑ Xu, Na; Tsai, Chia-Lun; Lee, Jeannie T. (2006-02-24). "Transient homologous chromosome pairing marks the onset of X inactivation". Science. 311 (5764): 1149–1152. Bibcode:2006Sci...311.1149X. doi:10.1126/science.1122984. ISSN   1095-9203. PMID   16424298. S2CID   20362477.
  21. ↑ Lee, J. T.; Strauss, W. M.; Dausman, J. A.; Jaenisch, R. (1996-07-12). "A 450 kb transgene displays properties of the mammalian X-inactivation center". Cell. 86 (1): 83–94. doi: 10.1016/s0092-8674(00)80079-3 . ISSN   0092-8674. PMID   8689690. S2CID   17888183.
  22. ↑ "Interview with Jeannie T. Lee, MD, PHD". 6 August 2013. Archived from the original on 19 April 2017. Retrieved 18 April 2017.
  23. ↑ "Centennial Awards honor outstanding GENETICS articles". EurekAlert!. Retrieved 2017-09-30.
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