Special Topic: Epigenetics

January 2013
REUTERS/Jason Reed
Epigenetics: 20 Years and Rising

The term “epigenetics” denotes control over the expression of genes in ways that are “above” or “in addition to” genetics itself. At the molecular level, it involves the addition of chemical markers to the DNA itself or to the histone proteins around which DNA is wrapped. The markers inactivate specific genes. More conceptually, we need epigenetics to explain, for example, that of two genetically identical twins, one may suffer autism or schizophrenia while the other does not.

As Adrian Bird of the University of Edinburgh recently noted in New Scientist, most definitions of “epigenetics” mention heritable changes within a cell that do not result from changes in DNA sequence, although the term actually encompasses “a vast array of molecular mechanisms that affect the activity of genes” (New Scientist, 217[2898]: i-viii, 5 January 2013).

The matter of whether genes are “expressed” or “silenced” by epigenetic activity, of course, has untold implications in many aspects of human physiology and health, including embryonic development and, later, susceptibility to disease—notably, some forms of cancer. Although much of epigenetic research has focused on cancer, recent years have seen an expansion into other areas of investigation, not only in disease but in behavioral or psychiatric manifestations of epigenetic influence passing through generations.

In all, epigenetics represents another reminder of how the ever-increasing knowledge of the genome has only underscored the daunting complexity of the biochemical and environmental factors at play in gene regulation and expression, not to mention the challenge of translating that knowledge into therapeutic interventions.

ScienceWatch first examined epigenetics as a Special Topic in 2009, based on a selection of pertinent papers indexed by Thomson Reuters between 1998 and 2008.

For the present survey, ScienceWatch decided on a deeper and more retrospective approach: 20 years of papers, published between 1992 and 2011. And, beyond searching for permutations of the term “epigenet*,” this study employed a detailed list of relevant keywords in an effort to capture the range of processes and agents involved in epigenetics. Such terms included “DNA methyl*,” “H3 lysine*,” “posttranslational modif*,” among many others. (See the “Methodology” tab below.)

The resulting sample consisted of more than 100,000 papers. From this selection, ScienceWatch identified the prominent players in epigenetics research over the last two decades. The accompanying tables feature highly cited and prolific authors, institutions, nations, and journals, along with a selection of most-cited papers. (To view this material, please see the designated tabs above, marked “Authors,” “Institutions,” “Papers,” etc.)

Papers on epigenetics, 1992 to 2011

One measure is telling in itself: the graph showing the annual number of epigenetics papers indexed by Thomson Reuters over the 20-year period, illustrating an eight-fold increase from just over 1,000 papers in 1992 to more than 8,500 in 2011.

Following on this steady rise, epigenetics as a research field will undoubtedly get a further boost from the 2012 Nobel Prize in Physiology or Medicine, awarded to John B. Gurdon and Shinya Yamanaka. Gurdon showed that an adult frog nucleus contains all the genetic information needed to develop into a mature frog. Yamanaka discovered that just four genes could reprogram an adult skin cell into a pluripotent stem cell, capable of differentiating into all the specialized cell lines of an adult mouse. Both were effectively reversing a lifetime of epigenetic modifications to the cell.

When ScienceWatch last looked at epigenetics in 2009, a major research focus was the role of epigenetics in cancer and the mechanisms of DNA methylation, which linked environmental carcinogens to tumor formation. A fresh look at papers published since then reveals that many of the same topics remain of interest, but with additional areas coming to the fore. One highly cited paper, for example, comes from a group of researchers at McGill University in Montreal, Canada, who show that the altered response to stress of abused children is the result of epigenetic modifications to a specific glucocorticoid receptor molecule. The changes show up in brain tissue from suicides who were victims of child abuse, but not in suicides who were not abused or controls. (P.O. McGowan, et al., “Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse,” Nature Neuroscience, 12(3): 342-8, 2009; currently cited 473 times in Web of Science.)

This research, linking epigenetic events to observable changes in behavior, is a prominent aspect of more recent research. The effects of malnutrition during pregnancy, for example, are seen not only in the children of malnourished mothers, but in their grandchildren, too, and possibly beyond. Highly cited in nutrition and epigenetics is a paper by Sir Peter Gluckman, University of Auckland in New Zealand, and colleagues, reviewing epigenesis and chronic non-communicable diseases. It is a mismatch of conditions between early and late environments that seems to be the problem. Children of malnourished mothers faced with limited food in later life seem to do okay. Those who have an abundance of food develop cardiovascular and metabolic diseases. Epigenetic control is thus adaptive. (P.D. Gluckman, et al., “Epigenetic mechanisms that underpin metabolic and cardiovascular diseases,” Nature Reviews Endocrinology, 5(7): 401-8, 2009.)

Autoimmune diseases, too, are being explored through an epigenetic lens. A review by Anura Hewagama and Bruce Richardson, of the University of Michigan, investigates the ways in which environmental factors interact with specific predisposing genetic elements to trigger diseases such as lupus, multiple sclerosis and rheumatoid arthritis (A. Hewagama, et al., “The genetics and epigenetics of autoimmune diseases,” Journal of Autoimmunity, 33[1]: 3–11, 2009; 92 citations.)

The modern blossoming of epigenetics—from molecular mechanisms to effects on the organism as a whole—is a splendid vindication of Conrad Waddington’s original (1942) definition of the subject as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being” (C.H. Waddington, Endeavour, 1, 18–20, 1942.) Waddington’s “epigenetic landscape” imagines the organism as a ball poised at the top of a hill, free to roll down a series of valleys to the final phenotype below. The landscape as a whole represents the genome of the organism, and as the organism develops it traces a route through the valleys. Its route is conditioned by epigenetic changes, the ridges between the valleys representing successive constraints. Gurdon and Yamanaka showed how the ball can be pushed back up to the top of the valley, where all things permitted by the genome are once again possible. Modern epigenetic research is determining the underlying orogenic forces, which throw up the ridges that guide the organism’s development and, in some cases, finding ways to kick the ball out of one valley and into an adjacent one that may result in a longer or smoother journey through life.

Highly Cited Authors in Epigenetics, 1992 to 2011

(Listed in alphabetical order, based on papers published in Special Topics epigenetics database)

Name Affiliation
C. David Allis Rockefeller University, New York, USA
Stephen B. Baylin Johns Hopkins University School of Medicine, Baltimore, MD, USA
Timothy H. Bestor Columbia University Medical Center, New York, NY, USA
Adrian P. Bird University of Edinburgh, UK
Hediye Erdjument- Bromage Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Manel Esteller Bellvitge Institute for Biomedical Research and University of Barcelona School of Medicine, Barcelona, Spain
James G. Herman Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jean-Pierre J. Issa Temple University School of Medicine, Philadelphia, PA, USA
Rudolf Jaenisch Massachusetts Institute of Technology and Whitehead Institute for Biomedical Research, Cambridge, MA, USA
Thomas Jenuwein Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
Peter A. Jones University of Southern California, Los Angeles, CA, USA
Tony Kouzarides University of Cambridge, Cambridge, England
Arthur M. Krieg RaNA Therapeutics, Cambridge, MA, USA
En Li China Novartis Institutes for BioMedical Research, Shanghai, China
Paul A. Marks Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Yoshiro Nakatani Dana-Farber Cancer Institute, Boston, MA, USA
Wolf Reik Babraham Institute, Cambridge, UK
Danny Reinberg New York University Langone Medical Center, New York, NY, USA
Michael G. Rosenfeld University of California, San Diego, La Jolla, CA, USA
Stuart L. Schreiber Harvard University and the Broad Institute, Cambridge, MA, USA
David Sidransky Johns Hopkins University School of Medicine, Baltimore, MD, USA
Paul Tempst Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Jerry L. Workman Stowers Institute for Medical Research, Kansas City, MO, USA
Yi Zhang Harvard University School of Medicine and Boston Children’s Hospital, Boston, MA, USA
SOURCE: Thomson Reuters Web of Knowledge

 

Epigenetics: Highly Cited Institutions, 1992-2011

(Listed by number of total citations to papers in Special Topics epigenetics database)

Institution Citations
Harvard University 172,775
Johns Hopkins University 116,904
National Cancer Institute (USA) 68,595
MIT 63,408
University of Calif., Los Angeles 50,867
University of Calif., San Francisco 49,246
University of Calif., San Diego 48,690
University of Pennsylvania 48,233
University of Cambridge 46,288
Baylor College of Medicine 45,712
University of Southern California 43,182
Memorial Sloan-Kettering Cancer Ctr. 41,529
University of Virginia 40,572
University of Edinburgh 39,450
University of North Carolina 39,263
SOURCE: Thomson Reuters Web of Knowledge

Epigenetics: High-Impact Institutions, 1992-2011

(Listed by average cites per paper, among institutions with 300 or more papers in Special Topics epigenetics database)

Institution Cites per Paper
MIT 101.3
Cold Spring Harbor Laboratory 87.85
University of Virginia 74.99
Memorial Sloan-Kettering Cancer Ctr. 68.42
Natl. Inst. of Child Health & Human Development (USA)  

67.29

Massachusetts General Hospital 65.26
University of Edinburgh 64.46
University of Calif., San Diego 64.15
Fred Hutchinson Cancer Res. Ctr. 64.02
Harvard University 58.87
Rockefeller University 57.67
University of Iowa 56.56
Johns Hopkins University 56.34
University of Southern California 53.71
Japan Science and Technology Agency 52.25
SOURCE: Thomson Reuters Web of Knowledge

Epigenetics: Prolific Institutions, 1992-2011

(Listed by number of papers in Special Topics epigenetics database)

Institution Number of Papers
Harvard University 2,935
Johns Hopkins University 2,075
National Cancer Institute (USA) 1,706
University of Tokyo 1,197
University of Calif., Los Angeles 1,155
U. Texas M.D. Anderson Cancer Ctr. 1,131
University of Pennsylvania 1,127
University of Calif., San Francisco 1,108
Max Planck Society 956
University of Cambridge 951
University of Michigan 928
Baylor College of Medicine 924
University of Washington 909
University of North Carolina 899
Ohio State University 892
SOURCE: Thomson Reuters Web of Knowledge

Epigenetics: Highly Cited Nations, 1992-2011

(Listed by number of total citations to papers in Special Topics epigenetics database)

Nation Citations
USA 1,710,376
UK 328,507
Germany 245,928
Japan 208,344
France 164,355
Canada 150,222
Italy 91,252
Netherlands 86,076
Australia 80,929
Switzerland 69,774
Spain 65,611
Austria 57,118
China 46,120
Sweden 45,823
Belgium 37,476
SOURCE: Thomson Reuters Web of Knowledge

Epigenetics: High-Impact Nations, 1992-2011

(Listed by average citations per paper, of those nations that published 500 or more papers in Special Topics epigenetics database)

Nation Cites per Paper
Austria 45.69
USA 36.14
UK 35.88
Switzerland 33.27
Israel 32.20
Netherlands 32.02
Denmark 30.71
Belgium 30.13
Australia 30.06
Canada 28.79
Germany 27.66
France 27.61
Sweden 26.80
Finland 26.36
Norway 23.68
SOURCE: Thomson Reuters Web of Knowledge

Epigenetics: Prolific Nations, 1992-2011

(Listed by number of papers in Special Topics epigenetics database)

Nation Number of Papers
USA 47,320
Japan 9,325
UK 9,115
Germany 8,891
France 5,952
Canada 5,218
China 4,822
Italy 4,279
Spain 2,830
Australia 2,692
Netherlands 2,688
South Korea 2,478
Switzerland 2,097
Sweden 1,710
Austria 1,250
SOURCE: Thomson Reuters Web of Knowledge

Epigenetics: Highly Cited Journals, 1992-2011

(Listed by number of total citations to papers in Special Topics epigenetics database)

Institution Citations
PNAS 143,507
Journal of Biological Chemistry 119,268
Nature 116,371
Cell 114,531
Molecular Cell Biology 89,970
Cancer Research 89,458
Genes & Development 68,178
Science 67,566
Nature Genetics 58,683
EMBO Journal 54,548
Molecular Cell 50,858
Oncogene 50,261
Nucleic Acids Research 36,034
Human Molecular Genetics 28,179
Blood 27,168
SOURCE: Thomson Reuters Web of Knowledge

Epigenetics: High-Impact Journals, 1992-2011

(Listed by average cites per paper, of those that published 300 or more papers in Special Topics epigenetics database)

Journal Cites per Paper
Nature 200.64
Cell 174.86
Science 164.80
Nature Genetics 138.73
Genes & Development 100.41
Molecular Cell 77.53
EMBO Journal 71.68
PNAS 68.30
Cancer Research 57.46
Current Biology 54.48
Molecular Cell Biology 48.95
Development 48.61
Human Molecular Genetics 47.76
Journal of Immunology 43.84
Oncogene 40.50
SOURCE: Thomson Reuters Web of Knowledge

Epigenetics: Prolific Journals, 1992-2011

(Listed by number of papers in Special Topics epigenetics database)

Journal Papers
Journal of Biological Chemistry 3,394
PNAS 2,101
Molecular Cell Biology 1,838
Cancer Research 1,557
Blood 1,490
Nucleic Acids Research 1,275
Oncogene 1,241
Biochemical and Biophysical Research Communications 1,052
PLOS ONE 1,038
Clinical Cancer Research 831
EMBO Journal 761
International Journal of Cancer 708
Genes & Development 679
Biochemistry 673
Molecular Cell 656
SOURCE: Thomson Reuters Web of Knowledge

Highly Cited Papers in Epigenetics, 1992 to 2011

(Drawn from the Special Topics epigenetics database, listed by citations in each five-year grouping)

1992-1996

Paper

Citations

J.G. Herman, et al., “Methylation-specific PCR: A novel PCR for methylation status of CpG islands, PNAS, 93(18): 9821-6, 1996. 3,486
A.M. Krieg, et al., “CpG motifs in bacterial DNA trigger direct B-cell activation,” Nature, 374(6522): 546-9, 1995. 2,160
E. Li, T.H. Bestor, R. Jaenisch, “Targeted mutation of the DNA methyltransferase gene results in embryonic lethality,” Cell, 69(6): 915-26, 1992. 2,031
V.V Ogryzko, et al., “The transcriptional coactivators p300 and CBP are histone acetyltransferases,” Cell, 87(5): 953-9, 1996. 1,772
A. Merlo, et al., “5’ CpG island methylation is associated with transcriptional silencing of the tumor-suppressor p16/CDKN2/MTS1 in human cancers,” Nature Medicine, 1(7): 686-92, 1995. 1,440

1997-2001

Paper Citations
B.D. Strahl, C.D. Allis, “The language of covalent histone modifications,” Nature, 403(6765): 41-5, 2000. 3,225
H. Hemmi, et al., “A Toll-like receptor recognizes bacterial DNA,” Nature, 408(6813): 740-5, 2000. 3,088
M. Okano, et al., “DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development,” Cell, 99(3): 247-57, 1999. 1,618
X.S. Nan, et al., “Transcriptional repression by the methyl-CpG-binding protein McCP2 involves a histone deacetylase complex,” Nature, 393(6683): 386-9, 1998. 1,532
M. Grunstein, “Histone acetylation in chromatin structure and transcription,” Nature, 389(6649): 349-52, 1997. 1,489

2002-2006

Paper Citations
A. Subramanian, et al., “Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles,” PNAS, 102(43): 15545-50, 2005. 2,656
I.C.G. Weaver, et al., “Epigenetic programming by maternal behavior,” Nature Neuroscience, 7(8): 847-54, 2004. 1,342
B.E. Bernstein, et al., “A bivalent chromatin structure marks key developmental genes in embryonic stem cells,” Cell, 125(2): 315-26, 2006. 1,338
M.E. Hegi, et al., “MGMT gene silencing and benefit from temozolomide in glioblastoma,” New Engl. J. Med., 352(10): 997-1003, 2005. 1,283
T.A. Volpe, et al., “Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi,” Science, 297(5588): 1833-7, 2002. 1,020

2007-2011

Paper Citations
K. Takahashi, et al., “Induction of pluripotent stem cells from adult human fibroblasts by defined factors,” Cell, 131(5): 861-72, 2007. 3,041
A. Barski, et al., “High-resolution profiling of histone methylations in the human genome,” Cell, 129(4): 823-37, 2007. 1,604
K. Okita, et al., “Generation of germline-competent induced pluripotent stem cells,” Nature, 448(7151): 313, 2007. 1,349
T.S. Mikkelsen, et al., “Genome-wide maps of chromatin state in pluripotent and lineage-committed cells,” Nature, 448(7153): 553, 2007. 1,122
M. Wernig, et al., “In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state,” Nature, 448(7151): 318, 2007. 1,116
SOURCE: Thomson Reuters Web of Knowledge

Epigenetics: Most-Represented Fields, 1992-2011

(Listed by number of papers in Special Topics epigenetics database, as indexed in respective Web of Science journal categories

Journal Category Papers
Biochemistry & Molecular Biology 29,891
Cell Biology 16,579
Oncology 14,799
Genetics & Heredity 14,020
Neurosciences 4,722
Biotechnology & Applied Microbiology 4,453
Pharmacology & Pharmacy 4,436
Hematolology 4,004
Biophysics 3,365
Immunology 3,313
Developmental Biology 3,188
Plant Sciences 3,179
Medicine, Research & Experimental 3,124
Biology 2,887
Endocrinology & Metabolism 2,778
SOURCE: Thomson Reuters Web of Knowledge

The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.