国立遺伝学研究所

Physics of Life Reviews 8 (2011) 51–52
www.elsevier.com/locate/plrev
Comment
Irregular folding of nucleosomes in the cell
Comment on “Cracking the chromatin code: Precise rule of
nucleosome positioning” by Edward N. Trifonov
Hideaki Takata a , Kazuhiro Maeshima a,b,∗
a Biological Macromolecules Laboratory, Structural Biology Center, National Institute of Genetics, Mishima, Shizuoka, 411-8540 Japan
b Department of Genetics, School of Life Science, Graduate University for Advanced Studies (Sokendai), Mishima, Shizuoka, 411-8540 Japan
Received 18 January 2011; accepted 19 January 2011
Available online 20 January 2011
Communicated by M. Frank-Kamenetskii
Keywords: DNA; Nucleosome; Chromatin; Chromosome; Irregular folding; Genome; Repetitive DNA sequences
The human body consists of 60 trillion cells, each of which has a total of 2 meters of DNA in the nucleus with a
diameter of approximately 10 µm. DNA carries a negatively charged phosphate backbone that produces electrostatic
repulsion between adjacent DNA molecules, making it difficult for DNA to coordinate its own folding [1,2]. For the
primary level of folding, a negatively charged DNA molecule is wrapped around the basic core, a histone octamer,
which consists of the two sets of histones, H2A, H2B, H3, and H4 proteins, and forms a nucleosome structure [3].
Within the nucleosome fibers, where each nucleosome is connected by linker DNA like “beads on a string” [4],
how can the histone octamer “see” DNA sequences? Trifonov have provided a thought-provoking review describing
the nucleosome positioning signal present on DNA sequences [5]. Surprisingly, three different approaches revealed
the same unique sequence motif (CGRAAATTTYCG)n , or (YRRRRRYYYYYR)n in binary form [5]. Since genome
functions such as DNA replication, recombination, repair and gene transcription are all dependent upon accessibility
to DNA, the nucleosome positioning would represent the “chromatin code”. Therefore, the physico-chemical features
of the nucleosome positioning can be analyzed to reveal information regarding the regulation of genome functions.
Several interesting questions surrounding nucleosome positioning have emerged from the review [5]: for example, is the identified sequence motif or the 10–11 base pair periodicity conserved in prokaryotes that do not have
nucleosomes? Why are the histone proteins in eukaryotes highly conserved whereas genome sequences and the positioning sequence motif are quite divergent among organisms? Which classes of proteins can recognize the positioning
motif, the histone octamer itself, histone chaperones, and/or remodeling proteins? Can the epigenetic mark, histone
modifications, affect the nucleosome positioning?
DOI of original article: 10.1016/j.plrev.2011.01.004.
* Corresponding author at: Biological Macromolecules Laboratory, Structural Biology Center, National Institute of Genetics, 1111, Yata,
Mishima, Shizuoka, 411-8540, Japan. Fax: +81 55 981 6864.
E-mail address: [email protected] (K. Maeshima).
1571-0645/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.plrev.2011.01.005
52
H. Takata, K. Maeshima / Physics of Life Reviews 8 (2011) 51–52
Since the nucleosome structure and precise rule of nucleosome positioning are well described by Trifonov [5], we
would like to focus more on the higher order structures formed by nucleosomes. As Trifonov reported, when chromatins are digested with “bulky” nucleases to prepare dinucleosomes, significant size variation of the DNA fragments
in the dinucleosomes is observed, suggesting that a diversity of linker DNA length exists in the nucleosome arrays [5].
The size variation of the linker DNA would provide structural flexibility for the nucleosome–nucleosome interaction.
This implies that an irregular configuration of nucleosomes is formed, as opposed to the formation of regular 30 nm
chromatin fibers. The reason for this is as follows: the formation of the 30 nm chromatin fibers requires the selective
binding of nucleosomes, which are spatially close on the DNA strand [6]. The size diversity of the linker DNA would
disrupt the selective binding of nucleosomes and formation of the 30 nm chromatin fiber. However, the importance of
this linker size variation was not appreciated, as the nucleosome has long been assumed to fold into the regular 30 nm
chromatin fibers [6].
Recently, when frozen hydrated human mitotic cells were observed using cryo-electron microscopy, higher order
structures, including 30 nm chromatin fibers, were not found [7]. Cryo-electron microscopy remains one of the best
ways to visualize chromosomes in their intact, native state [8]. Subsequent image processing revealed an 11 nm, but
not 30 nm, periodicity in the obtained images [7]. Thus, we proposed that chromosomes consist mainly of irregularly
folded nucleosome fibers lacking 30 nm chromatin fibers, which is similar to a “polymer melt” [6,7,9,10]. Based on
this and other available observations we also assumed that a similar state exists in the majority of active interphase
nuclei [6,10].
The concept of the polymer melt implies that polymer chains exist in a dynamic state [11]: nucleosome fibers may
be constantly moving and rearranging at the local level. We also proposed that these local dynamics would have several
advantages in various genome functions such as DNA replication, recombination, repair and gene transcription during
interphase, and also chromosome condensation and segregation during mitosis [6,7,10]. For the local movements
of each nucleosome, it would be intriguing to investigate how flexible the linker DNA, whose persistence length is
approximately 150 nucleotides (50 nm), would be in the cells.
Another interesting point regarding the higher order structure of the genome is the repetitive DNA sequences within
the genome itself. Upon completion of the human genome sequencing project we learned that the human genome is
full of repetitive DNA sequences [12]. Although we proposed that chromosomes consist mainly of irregularly folded
nucleosome fibers, it is reasonable to postulate that the nucleosomes on periodic sequences, which can have regular
linker DNA, could form regular fiber structures such as the 30 nm chromatin fibers. How often is the identified sequence motif found in the satellite DNA clustered in the centromere [13], and also in the short interspersed nuclear
elements (SINEs) and long interspersed nuclear elements (LINEs) [14], which are scattered throughout the genome?
Since the nucleosome positioning would represent the “chromatin code”, investigation of the nucleosome positioning in the repetitive sequences might provide a number of clues for answering the following big questions: Are the
repetitive sequences really “junk”? and, Do they have any cellular functions?
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