Page 19 - Academic Press Encyclopedia of Physical Science and Technology 3rd Molecular Biology

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Encyclopedia of Physical Science and Technology EN002G-104 May 17, 2001 20:53

Chromatin Structure and Modification 811

the resulting entity—chromatin—presents the genome as “nuclein.” In 1889, work by R. Altmann demonstrated
in compact, interpretable, and soluble form, and—most that it consists of nucleic acid and protein. A functional
importantly—enables a remarkably rapid response to a connection between either of these two chemical sub-
great variety of internal and external stimuli. stances and the phenomenon of heredity remained elusive,
however.
In the 1900–1920s, studies by T. H. Morgan and a dis-
II. CHROMATIN: A BRIEF tinguished pleiade of his junior colleagues (C. B. Bridges,
HISTORY OF SCHOLARSHIP H. K. Muller, and A. H. Sturtevant) in the fruit fly
Drosophila melanogaster physically placed genes onto
Cytological, genetic, biochemical, and biophysical stud- chromosomes, connecting genetics and cytology. Bio-
ies of the past 100 years have offered many insights into chemical analysis performed by A. Kossel in the 1890s–
the structure of chromatin and chromosomes and into the 1910s led to the discovery of histones and protamines—
mechanistic aspects of its role in enabling gene expression the small, highly positively charged protein components of
and chromosome behavior. Our current notions of chro- chromosomes. Their apparent biochemical diversity, cou-
matin structure and function offer interesting testimony to pled with a notion of DNA as a chemically monotonous
the validity of T. Kuhn’s well-known thesis on the role of entity, prompted the belief into their role as carriers of ge-
“paradigms” in scientific inquiry. The first half of the 20th netic information. This theory was placed in very strong
century witnessed the protein constituents of the nucleus doubt in 1944 by work of O. T. Avery, C. M. MacLeod,
being awarded the role of carriers of genetic information, and M. McCarty at the Rockefeller Institute, and firmly
with DNA relegated to a minor role of a scaffold. After the laid to rest in 1952 by A. D. Hershey and M. Chase at the
discovery of the nucleosome in 1973–1974, some 20 years Cold Spring Harbor Laboratory.
of scholarship in eukaryotic transcription proceeded under After a combined effort by chemists and X-ray crys-
the auspices of notions developed in studying gene regu- tallographers, including P. Levene, A. Todd, E. Chargaff,
lation in bacteria, and thus the histones underwent quite R. E. Franklin, and M. H. F. Wilkins, made their indeli-
the proverbial reversal of fortune and were considered a ble contribution to the 1953 discovery by J. D. Watson
repressive, obstructive scaffold instead; bona fide tran- and F. H. C. Crick that DNA is a double helix, a 20-
scriptional control was only thought to occur on stretches year avalanche of experimentation revealed the foundation
of naked, histone-free DNA. of genetic information maintenance and transfer in living
Following the genetic and biochemical characterization systems, mostly prokaryotes. This period witnessed three
of complex machines that modify chromatin in the mid- very important studies that implicated chromatin in effect-
1990s, the past few years have offered a dramatic and ing eukaryotic gene regulation.
emphatic shift in our appreciations of its intranuclear func- Cytological studies of mammalian cells have revealed
tion: no longer viewed as monotonous or merely repres- an interesting gender bias: the interphase (i.e., nondi-
sive, chromatin is now considered an essential component viding) nuclei of female, but not male, cells contained
of most gene regulatory pathways in vivo.Wenow see a small, microscopically dense entity termed the “Barr
the nucleus as populated with enzymatic complexes that body.” In 1958, work from S. Ohno demonstrated that
remodel chromatin in a targeted fashion to achieve a wide this entity corresponds to one of the two X chromosomes
variety of regulatory responses from the DNA. The current in the female karyotype. Soon after, in 1961, genetic
view of transcriptional and genomic control, therefore, is experiments by M. Lyon showed that the female genome
one of a complex and mutually beneficial symbiosis be- is functionally hemizygous for sex-linked loci—i.e., that
tween the protein regulators of the genome and the nucle- of the two X chromosomes in mammalian females, one
oprotein architecture of chromatin. is genetically silent (this phenomenon is known as “X
The etymology of the term “chromatin” traces its ori- chromosome inactivation”). The combination of these
gins to cytological studies of the late 19th century, when data provided evidence for a correlation between the
“thread-like structures”—chromosomes—were revealed structure of specific chromosomes and their state of ac-
in dividing cells by staining with dyes. These were pre- tivity. In recent years, work from many laboratories, most
sumed to consist of “chromatin” (a term proposed by W. notably those of S. Tilghman and R. Jaenisch, offered
Waldeyer in 1888) whose chemical nature was completely several remarkable insights into the mechanistic aspects
obscure. Fortunately for science, the contemporaneous of X chromosome inactivation (see below). Importantly,
discovery by F. Miescher of DNA in human lympho- observations made by Ohno and Lyon extended earlier
cytes eventually prompted an analysis into whether the (1928) studies by E. Heitz on plant chromosomes, which
substance of chromosomes is in any way related to the lead to the discovery that the contents of the nucleus
chemical entity extracted by Miescher from cells known can be divided into heterochromatin and euchromatin,