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Nucleosomes function and design

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1 Nucleosomes function and design on Sat Jun 20, 2015 8:38 am

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Nucleosomes and irreducible complexity

http://reasonandscience.heavenforum.org/t2051-nucleosomes-function-and-design#3509

A nucleosome is a basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound in sequence around eight  histone protein cores. This structure is often compared to thread wrapped around a spool. The basic level of DNA compaction is the nucleosome, where the double helix is wrapped around the histone octamer containing two copies of each histone H2A, H2B, H3 and H4Linker histone H1 binds the DNA between nucleosomes and facilitates packaging of the 10 nm "beads on the string" nucleosomal chain into a more condensed 30 nm fiber.

Histones are among the most highly conserved eucaryotic proteins. For example, the amino acid sequence of histone H4 from a pea and from a cow differ at only 2 of the 102 positions. This strong evolutionary conservation suggests that the functions of histones involve nearly all of their amino acids, so that a change in any position is deleterious to the cell. This suggestion has been tested directly in yeast cells, in which it is possible to mutate a given histone gene in uitro andintroduce it into the yeast genome in place of the
normal gene. As might be expected, most changes in histone sequences are lethal; the few that are not lethal cause changes in the normal pattern of gene expression, as well as other abnormalities.

If a change in histone sequences are lethal, how could it probably come to be in gradual steps, or trial and error ? As long as the correct sequence is not reached, no function.....

Nucleosome assembly following DNA replication, DNA repair and gene transcription is critical for the maintenance of genome stability and epigenetic information.

In assembling a nucleosome, the histone folds first bind to each other to form H3-H4 and H2A-H2B dimers, and the H3-H4 dimers combine to form tetramers. An H3-H4 tetramer then further combines with two HZA-H2B dimers to form the compact octamer core, around which the DNA is wound

The  assembly is a sequential  multistep process, requiring several  folds and steps in a highly organized, regulated and precise manner, and must have been programmed and functional right from the beginning.   Histone chaperones play important roles in regulating the intricate steps involved in folding of histones together with DNA to form correctly assembled nucleosomes, furthermore  assembly, disassembly and histone exchange to facilitate DNA replication, repair and transcription. There is a need for histone chaperones to guide the process and each step along the assembly pathway is carefully controlled and regulated by these histone chaperones. It is evident that a stepwise evolutionary fashion of development of histone chaperones to guide the process would result in a disaster. They had to be there fully working and programmed to do their job right from the start.  
Furthermore, to add to the already amazing machine like performance,  (linker histones) have to participate at each step in the processes of nucleosome assembly, disassembly and histone exchange during different genomic processes.   Linker histone H1 is an essential component of chromatin structure ( so its irreducible ).  H1 links nucleosomes into higher order structures.

Nucleosome formation is dependent on the positive charges of the H4 histones and the negative charge on the surface of H2A histone fold domains. Acetylation of the histone tails disrupts this association, leading to weaker binding of the nucleosomal components. Histone acetyltransferases (HATs) and Histone deacetylase ( HDAC ) are also essential enzymes, that  remove through acetylation the  positive charge on the histones, and as a consequence, the condensed chromatin is transformed into a more relaxed structure that is associated with greater levels of gene transcription. This relaxation can be reversed by HDAC activity.

So we can conclude that all these parts, DNA,  Linker histone H1, histones H2A, H2B, H3 and H4,and acetyltransferases (HATs) and Histone deacetylase ( HDAC ) form a  set of well-matched, mutually interacting, nonarbitrarily individuated parts such that each part in the set is indispensable to maintaining the system's basic, and therefore original, function.  The set of these indispensable parts is known as the irreducible core of the system, while Histone chaperones are also essential to build the since they guide the process and each step along the assembly pathway.








Nucleosomes function and design 14

A nucleosome is a basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound in sequence around eight  histone protein cores. This structure is often compared to thread wrapped around a spool.

Nucleosomes form the fundamental repeating units of eukaryotic chromatin, which is used to pack the large eukaryotic genomes into the nucleus while still ensuring appropriate access to it (in mammalian cells approximately 2 m of linear DNA have to be packed into a nucleus of roughly 10 µm diameter). Nucleosomes are folded through a series of successively higher order structures to eventually form a chromosome; this both compacts DNA and creates an added layer of regulatory control, which ensures correct gene expression. Nucleosomes are thought to carry epigenetically inherited information in the form of covalent modifications of their core histones.

“the information storage density of DNA, thanks largely to nucleosome spooling, is several trillion times that of the most advanced computer chips.”  15
So not only is there real information stored in DNA, but it is stored at a density on a molecular level, we can’t even approach with our best computers.

Dr. Stephen C. Meyer in his 1996 essay The Origin of Life and the Death of Materialism, wrote that

"the information storage density of DNA, thanks in part to nucleosome spooling, is several trillion times that of our most advanced computer chips 16


There are about 30 million nucleosomes in each human cell. So many are needed because the DNA strand wraps around each one only 1.65 times, in a twist containing 147 of its units, and the DNA molecule in a single chromosome can be up to 225 million units in length. 17

DNA has a striking property to pack itself in the appropriate solution conditions with the help of ions and other molecules. Usually, DNA condensation is defined as "the collapse of extended DNA chains into compact, orderly particles containing only one or a few molecules" 18

The basic level of DNA compaction is the nucleosome, where the double helix is wrapped around the histone octamer containing two copies of each histone H2A, H2B, H3 and H4. Linker histone H1 binds the DNA between nucleosomes and facilitates packaging of the 10 nm "beads on the string" nucleosomal chain into a more condensed 30 nm fiber. Most of the time, between cell divisions, chromatin is optimized to allow easy access of transcription factors to active genes, which are characterized by a less compact structure called euchromatin, and to alleviate protein access in more tightly packed regions called heterochromatin. During the cell division, chromatin compaction increases even more to form chromosomes, which can cope with large mechanical forces dragging them into each of the two daughter cells.

The Structure of the Nucleosome core Particle reveals how DNA ls packaged

The high-resolution structure of a nucleosome core particle, solved in 1997,
revealed a disc-shaped histone core around which the DNAwas tightlywrapped
1.7 turns in a left-handed coil



All four of the histones that make
up the core of the nucleosome are relatively small proteins (102-135 amino
acids), and they share a structural motif, known asthe histonefold,formed from
three cr helices connected by two loops



In assembling a nucleosome, the histone folds first bind to each other to form
H3-H4 and H2A-H2B dimers, and the H3-H4 dimers combine to form tetramers.
An H3-H4 tetramer then further combines with two HZA-H2B dimers to form the
compact octamer core, around which the DNA is wound

My contention is that the sequence of correct assembly is a multistep process, requiring several sequential
folds and steps in a highly organized and precise manner,  must have been fully functional right from the beginning.
The right process and sequence must be programmed. The presence of histone chaperone proteins, which are specific, and
could not have been co-opted from other systems, is essential.  Histone chaperones promote chromatin assembly,
disassembly and histone exchange to facilitate DNA replication, repair and transcription. Its not feasable that they
arose in a stepwise fashion, no function would be granted unless they were fully developed to exercise its specific function.




Histone chaperone proteins :

Histone chaperones in nucleosome assembly 19

Nucleosome assembly following DNA replication, DNA repair and gene transcription is critical for the maintenance of genome stability and epigenetic information. Nucleosomes are assembled via replication-coupled or replication-independent pathways with the aid of histone chaperone proteins. How these different nucleosome assembly pathways are regulated remains relatively unclear. Recent studies have provided insight into the mechanisms and the roles of histone chaperones regulating nucleosome assembly.

Following DNA replication during S phase, nucleosomes are assembled, using both parental histones and newly synthesized histones, in a process called replication-coupled nucleosome assembly. Nucleosome assembly during gene transcription and histone exchange occur throughout the cell cycle in a replication-independent manner

Histone chaperone proteins have prominent roles in facilitating these processes as well as in replacing old histones with new canonical histones or histone variants during the process of histone exchange. Histone chaperones promote chromatin assembly, disassembly and histone exchange to facilitate DNA replication, repair and transcription. Beyond that, histone chaperones play important roles in regulating the intricate steps involved in folding of histones together with DNA to form correctly assembled nucleosomes.  20

Stepwise assembly and disassembly of nucleosomes mediated by histone chaperones  see below:
DNA is wrapped around two H3–H4 dimers and two H2A–H2B dimers to form the nucleosome core particle. The stepwise assembly, along with the different possible intermediates including the tetrasome and hexasome, are represented here. Histone chaperones mediate each step of the assembly/disassembly process. Histone H2A is depicted in yellow, H2B in red, H3 in blue, and H4 in green.



Histones and DNA fail to self-assemble into nucleosomes under physiological conditions because of the strong tendency for histones to associate non-specifically with DNA and form aggregates. Thus there is a need for histone chaperones to guide the process and each step along the assembly pathway is carefully controlled and regulated by these histone chaperones.

It is evident that a stepwise evolutionary fashion of development of histone chaperones to guide the process would result in a disaster. They had to be there fully working and programmed to do their job right from the start.

Many specialized chaperones for the histones that form the nucleosome core particle (core histones) and those that interact with the nucleosome core and the linker DNA (linker histones) participate at each step in the processes of nucleosome assembly, disassembly and histone exchange during different genomic processes

Location and function of linker histones 21

The linker histones, H1 and its variant forms, have been implicated in the formation of higher orders of chromatin structure and gene repression.

Outstanding amongst the many functions proposed for the linker histone are its ability to stabilize the nucleosomal particle structure and its participation in the condensation of the 'beads-on-a-string' fiber into higher order structures. This correlation between the presence of linker histones on chromatin and a compacted structure, which limits the access of components of the transcriptional machinery, has led to the suggestion that linker histones may function as generalized repressors of transcription

there is a "linker histone" called H1 (or H5 in avian species). The linker histones present in all multicellular eukaryotes are the most divergent group of histones, with numerous cell type- and stage-specific variant. Linker histone H1 is an essential component of chromatin structure ( so its irreducible ) H1 links nucleosomes into higher order structures. 22

The linker histones, which do not contain the histone fold motif, are critical to the higher-order compaction of chromatin, because they bind to internucleosomal DNA and facilitate interactions between individual nucleosomes.

A common feature of this protein family is a tripartite structure in which a globular (H15) domain of about 80 amino acids is flanked by two less structured N- and C-terminal tails. The H15 domain is also characterised by high sequence homology among the family of linker histones. The highly conserved H15 domain is essential for the binding of H1 or H5 to the nucleosome.

highly preserved means, it did not evolve, and " is essential " means, its irreducible.

H1/H5 are chromatin-associated proteins that bind to the exterior of nucleosomes and dramatically stabilize the highly condensed states of chromatin fibers; stabilization of higher order folding occurs through electrostatic neutralization of the linker DNA segments, through a highly positively charged carboxy- terminal domain known as the AKP helix (Ala, Lys, Pro); thought to be involved in specific protein-protein and protein-DNA interactions and play a role in suppressing core histone tail domain acetylation in the chromatin fiber 23  see below:

Conserved Protein Domain Family H15



Histone acetyltransferase  (HATs) 24

are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.
In general, histone acetylation is linked to transcriptional activation and associated with euchromatin. When it was first discovered, it was thought that acetylation of lysine neutralizes the positive charge normally present, thus reducing affinity between histone and (negatively charged) DNA, which renders DNA more accessible to transcription factors. Research has emerged, since, to show that lysine acetylation and other posttranslational modifications of histones generate binding sites for specific protein–protein interaction domains, such as the acetyllysine-binding bromodomain.[citation needed] Histone acetyltransferases can also acetylate non-histone proteins, such as nuclear receptors and other transcription factors to facilitate gene expression.

Histone deacetylase ( HDAC )
are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins.

The interface between DNA and histone is extensive: 142 hydrogen bonds
are formed between DNA and the histone core in each nucleosome. Nearly half
of these bonds form between the amino acid backbone of the histones and the
phosphodiester backbone of the DNA. Numerous hydrophobic interactions and
salt linkages also hold DNA and protein together in the nucleosome. For example,
more than one-fifth of the amino acids in each of the core histones are either
lysine or arginine (two amino acids with basic side chains), and their positive
charges can effectively neutralize the negatively charged DNA backbone. These
numerous interactions explain in part why DNA of virtually any sequence can be
bound on a histone octamer core. The path of the DNA around the histone core
is not smooth; rather, several kinks are seen in the DNA, as expected from the
nonuniform surface of the core. The bending requires a substantial compression
of the minor groove of the DNA helix. Certain dinucleotides in the minor groove
are especially easy to compress, and some nucleotide sequences bind the nucleosome
more tightly than others . This probably explains some
striking, but unusual, cases of very precise positioning of nucleosomes along a
stretch of DNA. For most of the DNA sequences found in chromosomes, however,
the sequence preference of nucleosomes must be small enough to allow
other factors to dominate, inasmuch as nucleosomes can occupy any one of a
number of positions relative to the DNA sequence in most chromosomal
regions.In addition to its histone fold, each of the core histones has an N-terminal
amino acid "tail", which extends out from the DNA-histone core . These histone
tails are subject to several different types of covalent modifications
that in turn control critical aspects of chromatin structure and function
.
As a reflection of their fundamental role in DNA function through controlling
chromatin structure, the histones are among the most highly conserved
eucaryotic proteins
. For example, the amino acid sequence of histone H4 from a
pea and from a cow differ at only 2 of the 102 positions. This strong evolutionary
conservation suggests that the functions of histones involve nearly all of their
amino acids, so that a change in any position is deleterious to the cell. This suggestion
has been tested directly in yeast cells, in which it is possible to mutate a
given histone gene in uitro andintroduce it into the yeast genome in place of the
normal gene. As might be expected, most changes in histone sequences are
lethal
; the few that are not lethal cause changes in the normal pattern of gene
expression, as well as other abnormalities.

If a chance in histone seuqences are lethal, how could it probably come to be in
gradual steps, or trial and error ?




Despite the high conservation of the core histones, eucaryotic organisms
also produce smaller amounts of specialized variant core histones that differ in
amino acid sequence from the main ones. As we shall see, these variants, combined
with a surprisingly large variety of covalent modifications that can be
added to the histones in nucleosomes, make possible the many different chromatin
structures that are required for DNA function in higher eucaryotes.

Nucleosomes have a dynamic structure and are frequently subjected to changes
catalyzed by ATP-dependent chromatin-remodeling complexes


For many years biologists thought that, once formed in a particular position on
DNA, a nucleosome remains fixed in place because of the very tight association
between its core histones and DNA. If true, this would pose problems for genetic
readout mechanisms, which in principle require rapid access to many specific
DNA sequences, as well as for the rapid passage of the DNA transcription and
replication machinery through chromatin. But kinetic experiments show that the
DNA in an isolated nucleosome unwraps from each end at rate of about 4 times
per second, remaining exposed for 10 to 50 milliseconds before the partially
unwrapped tructure recloses.Thus, most of the DNA in an isolated nucleosome
is in principle available for binding other proteins .
For the chromatin in a cell, a further loosening of DNA-histone contacts is
clearly required, because eucaryotic cells contain a large variety of ATP-dependent
chromatin remodeling complexes. The subunit in these complexes that
hydrolyzes ATP is evolutionarily related to the DNA helicases (discussed in
Chapter 5), and it binds both to the protein core of the nucleosome and to the
double-stranded DNA that winds around it. By using the energy of AIP hydrolysis
to move this DNA relative to the core, this subunit changes the structure of a
nucleosome temporarily, making the DNA less tightly bound to the histone core.
Through repeated cycles of ATP hydrolysis, the remodeling complexes can catalyze
nucleosome sliding, and by pulling the nucleosome core along the DNA
double helix in this way, they make the nucleosomal DNA available to other proteins
in the cell (Figure 4-25). In addition, by cooperating with negatively










14) http://en.wikipedia.org/wiki/Nucleosome
15) https://www.probe.org/mere-creation-science-faith-and-intelligent-design/
16) http://www.conservapedia.com/Creation_science
17) http://able2know.org/topic/72452-35
18) https://en.wikipedia.org/wiki/DNA_condensation
19) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004355/
20) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004086/
21) http://www.nature.com/nsmb/journal/v5/n12/full/nsb1298_1025.html
22) http://www.ebi.ac.uk/interpro/entry/IPR005818
23) http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=cl00073
24) https://en.wikipedia.org/wiki/Histone_acetyltransferase



Last edited by Admin on Mon Oct 19, 2015 12:37 pm; edited 6 times in total

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2 Nucleosomes function and design on Mon Jun 22, 2015 2:39 pm

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Nucleosomes and irreducible complexity

A nucleosome is a basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound in sequence around eight  histone protein cores. This structure is often compared to thread wrapped around a spool. The basic level of DNA compaction is the nucleosome, where the double helix is wrapped around the histone octamer containing two copies of each histone H2A, H2B, H3 and H4. Linker histone H1 binds the DNA between nucleosomes and facilitates packaging of the 10 nm "beads on the string" nucleosomal chain into a more condensed 30 nm fiber.

Histones are among the most highly conserved eucaryotic proteins. For example, the amino acid sequence of histone H4 from a pea and from a cow differ at only 2 of the 102 positions. This strong evolutionary conservation suggests that the functions of histones involve nearly all of their amino acids, so that a change in any position is deleterious to the cell. This suggestion has been tested directly in yeast cells, in which it is possible to mutate a given histone gene in uitro andintroduce it into the yeast genome in place of the
normal gene. As might be expected, most changes in histone sequences are lethal; the few that are not lethal cause changes in the normal pattern of gene expression, as well as other abnormalities.

If a change in histone sequences are lethal, how could it probably come to be in gradual steps, or trial and error ? As long as the correct sequence is not reached, no function.....

Nucleosome assembly following DNA replication, DNA repair and gene transcription is critical for the maintenance of genome stability and epigenetic information.

In assembling a nucleosome, the histone folds first bind to each other to form H3-H4 and H2A-H2B dimers, and the H3-H4 dimers combine to form tetramers. An H3-H4 tetramer then further combines with two HZA-H2B dimers to form the compact octamer core, around which the DNA is wound

The  assembly is a sequential  multistep process, requiring several  folds and steps in a highly organized, regulated and precise manner, and must have been programmed and functional right from the beginning.   Histone chaperones play important roles in regulating the intricate steps involved in folding of histones together with DNA to form correctly assembled nucleosomes, furthermore  assembly, disassembly and histone exchange to facilitate DNA replication, repair and transcription. There is a need for histone chaperones to guide the process and each step along the assembly pathway is carefully controlled and regulated by these histone chaperones. It is evident that a stepwise evolutionary fashion of development of histone chaperones to guide the process would result in a disaster. They had to be there fully working and programmed to do their job right from the start.  
Furthermore, to add to the already amazing machine like performance,  (linker histones) have to participate at each step in the processes of nucleosome assembly, disassembly and histone exchange during different genomic processes.   Linker histone H1 is an essential component of chromatin structure ( so its irreducible ).  H1 links nucleosomes into higher order structures.

Nucleosome formation is dependent on the positive charges of the H4 histones and the negative charge on the surface of H2A histone fold domains. Acetylation of the histone tails disrupts this association, leading to weaker binding of the nucleosomal components. Histone acetyltransferases (HATs) and Histone deacetylase ( HDAC ) are also essential enzymes, that  remove through acetylation the  positive charge on the histones, and as a consequence, the condensed chromatin is transformed into a more relaxed structure that is associated with greater levels of gene transcription. This relaxation can be reversed by HDAC activity.

So we can conclude that all these parts, DNA,  Linker histone H1, histones H2A, H2B, H3 and H4,and acetyltransferases (HATs) and Histone deacetylase ( HDAC ) form a  set of well-matched, mutually interacting, nonarbitrarily individuated parts such that each part in the set is indispensable to maintaining the system's basic, and therefore original, function.  The set of these indispensable parts is known as the irreducible core of the system, while Histone chaperones are also essential to build the since they guide the process and each step along the assembly pathway.

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Multiplexing Genetic and Nucleosome Positioning Codes: A Computational Approach

Eukaryotic DNA is strongly bent inside fundamental packaging units: the nucleosomes. It is known that their positions are strongly influenced by the mechanical properties of the underlying DNA sequence. Here we discuss the possibility that these mechanical properties and the concomitant nucleosome positions are not just a side product of the given DNA sequence, e.g. that of the genes, but that a mechanical evolution of DNA molecules might have taken place. We first demonstrate the possibility of multiplexing classical and mechanical genetic information using a computational nucleosome model. In a second step we give evidence for genome-wide multiplexing in Saccharomyces cerevisiae and Schizosacharomyces pombe. This suggests that the exact positions of nucleosomes play crucial roles in chromatin function.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156905

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