Page 18 - Academic Press Encyclopedia of Physical Science and Technology 3rd Molecular Biology

P1: GNH Revised Pages
Encyclopedia of Physical Science and Technology EN002G-104 May 17, 2001 20:53

810 Chromatin Structure and Modification

Nucleosome A union of eight core histones, one linker I. THE 6-BILLION CHALLENGE
histone, and ca. 160 base pairs of DNA. The elementary
building block of the chromatin fiber. The functionality of the human genome—i.e., its capac-
Remodeling An ATP-dependent process of disrupting ity to control an extraordinarily complex program of cell
histone–DNA contacts in chromatin. Requires the ac- division, differentiation, and morphogenesis during em-
tion of dedicated macromolecular machines such as the bryonic development and adult ontogeny—is enabled in
SWI/SNF complex. An integral component of gene ac- the face of several formidable challenges.
tivation and repression. The first one is topological: the combined length of a
Transcription The process of RNA synthesis on a DNA single cell’s worth of human DNA is ca. 2.3 m (there
template. Catalyzed by RNA polymerase. are ∼6.6 × 10 base pairs of DNA in the diploid human
9
genome and each base pair is 0.32 nm long) and this ex-
traordinary quantity of nucleic acid—in the form of 46
COMPACTION of the eukaryotic genome into the nu- separate molecules—is packaged into that cell’s nucleus,
cleus must occur such that the instructions in the DNA i.e., a sphere with a diameter of ∼5 µM. Thus, the length
are accessible to molecular machines that effect replica- of the DNA fiber (which is 2 nm wide) exceeds that of its
tion, transcription, and repair. This challenging task is per- natural container by a factor of ∼500,000.
formed by uniting the DNA with histone proteins to yield The second challenge is that of the signal-to-noise ra-
chromatin—a dynamic, complex structure that controls tio: laden with molecular atavisms and genomic parasites,
the genome by both compacting and revealing it. Each the genome’s ∼800 Mb of genetic information (counting
180 base pairs of DNA is complexed with eight molecules each base pair as two bits, i.e., four base pairs per byte)
of core histone and one linker histone to yield the nucle- make Finnegan’s Wake seem lucid and succinct by com-
osome. A wide variety of modifications and alterations parison, since only ca. 20 Mb (∼3%) represent DNA that
of the nucleosomal fiber occur in vivo, including ATP- codes for protein. An even smaller fraction is “regulatory
dependent disruption of histone-DNA contacts, and the DNA”—i.e., stretches of the genome that contain molec-
covalent modification of the histone tails by acetylation. ular instructions on how and when its ∼40,000 genes are
The enzymatic machines that generate such modifications to be activated and silenced. The exact percentage of the
are targeted to specific loci in the genome by various reg- genome assigned to such regulatory function is unknown,
ulators to effect gene activation and repression. but a conservative estimate would be ca. 1% (8 Mb). Thus,
The enormously complex program of gene expres- the genome is a remarkably messy manual, in which a
sion that unfolds during ontogeny in eukaryotes is un- deluge of genetic gibberish (or, in less emphatic terms,
equivocally contingent on an accurate interpretation of of DNA to which we have not yet been able to assign a
the genome’s contents by transcriptional regulators. Their function) hides the occasional useful instruction or snip-
action is abetted by, and intimately functionally linked pet of data. The molecular complexes that have evolved
to, the native structure assumed by their DNA target in to interpret the genome—sequence-specific DNA binding
vivo: the nucleoprotein fiber of chromatin. This com- proteins and their cofactors—are thus challenged by a ma-
plex union of DNA with histone and other proteins jor problem of parsing the content of the genome in search
ensures that the genome is accommodated within the of relevant information.
nucleus by winding each 180 base pairs of DNA into a As if this were not enough, the physicochemical prop-
nucleosome, and by subsequent higher-order folding of erties of DNA—a very long polymer—make its aqueous
the nucleosomal fiber. Chromatin is not a passive scaffold, solutions extraordinarily viscous (as anyone who has ever
and undergoes a wide variety of structural transitions in worked with human genomic DNA knows from experi-
response to developmental, environmental, and internal ence, solutions of even 10 mg/ml cannot be pipetted if the
gene regulatory stimuli. A host of dedicated enzymatic DNA is not sheared first into fragments of smaller size).
complexes effect these transitions both in a genome-wide All interactions relevant to the biology of the genome,
(i.e., after DNA replication) and a localized fashion, when however, occur—and quite robustly—in an aqueous envi-
they are recruited by transcriptional regulators to medi- ronment that contains ∼100 mg/ml DNA (6–8pginca.
ate gene actvation or repression at specific loci. Unique 65 femtoliters)!
patterns of covalent post-translational histone modifica- All these challenges are very successfully met: in-
tion, and perturbation of histone-DNA contacts or higher- side the nucleus, the DNA of the genome finds itself a
order chromatin fiber structure that result from such tar- powerful ally as a large number of dedicated molecular
geting exert a potent regulatory effect on the underlying machines assemble it into a highly structured fiber by
DNA. winding it around specialized proteins called “histones”;