Scaffold/matrix attachment region

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S/MAR-functions: constitutive and facultative. A chromatin domain with constitutive S/MARs at its termini (I). When functional demands require the specific translocation of the constituent gene to the matrix, facultative S/MARs responds to topological changes which are initiated by the association of transcription factors (TF) and supported by histone acetylation. Topological changes are propagated once the gene is pulled through the transcriptional machinery (II). Transcription is terminated (III) followed by dissociation of the transcription complex (IV) SMARs facultative.png
S/MAR-functions: constitutive and facultative. A chromatin domain with constitutive S/MARs at its termini (I). When functional demands require the specific translocation of the constituent gene to the matrix, facultative S/MARs responds to topological changes which are initiated by the association of transcription factors (TF) and supported by histone acetylation. Topological changes are propagated once the gene is pulled through the transcriptional machinery (II). Transcription is terminated (III) followed by dissociation of the transcription complex (IV)

The term S/MAR (scaffold/matrix attachment region), otherwise called SAR (scaffold-attachment region), or MAR (matrix-associated region), are sequences in the DNA of eukaryotic chromosomes where the nuclear matrix attaches. As architectural DNA components that organize the genome of eukaryotes into functional units within the cell nucleus, S/MARs mediate structural organization of the chromatin within the nucleus. These elements constitute anchor points of the DNA for the chromatin scaffold and serve to organize the chromatin into structural domains. Studies on individual genes led to the conclusion that the dynamic and complex organization of the chromatin mediated by S/MAR elements plays an important role in the regulation of gene expression.

Contents

Overview

It has been known for many years that a polymer meshwork, a so-called "nuclear matrix" or "nuclear-scaffold" is an essential component of eukaryotic nuclei. This nuclear skeleton acts as a dynamic support for many specialized events concerning the readout a spread of genetic information (see below).

S/MARs map to non-random locations in the genome. They occur at the flanks of transcribed regions, in 5´-introns, and also at gene breakpoint cluster regions (BCRs). Being association points for common nuclear structural proteins S/MARs are required for authentic and efficient chromosomal replication and transcription, for recombination and chromosome condensation. S/MARs do not have an obvious consensus sequence. Although prototype elements consist of AT-rich regions several hundred base pairs in length, the overall base composition is definitely not the primary determinant of their activity. Instead, their function requires a pattern of "AT-patches" that confer the propensity for local strand unpairing under torsional strain.

Bioinformatics approaches support the idea that, by these properties, S/MARs not only separate a given transcriptional unit (chromatin domain) from its neighbors, but also provide platforms for the assembly of factors enabling transcriptional events within a given domain. An increased propensity to separate the DNA strands (the so-called 'stress induced duplex destabilization' potential, SIDD) can serve the formation of secondary structures such as cruciforms or slippage structures, which are recognizable features for a number of enzymes (DNAses, topoisomerases, poly(ADP-ribosyl) polymerases and enzymes of the histone-acetylation and DNA-methylation apparatus). S/MARs have been classified as either being constitutive (acting as permanent domain boundaries in all cell types) or facultative (cell type- and activity-related) depending on their dynamic properties.

While the number of S/MARs in the human genome has been estimated to approach 64,000 (chromatin domains) plus an additional 10,000 (replication foci), in 2007 still only a minor fraction (559 for all eukaryotes) had met the standard criteria for an annotation in the S/MARt database. [1]

Context-dependent properties

Current views of the nuclear matrix envision it as a dynamic entity, which changes its properties along the requirements of the cell nucleus—much the same as the cytoskeleton adapts its structure and function to external signals. In retrospect it is of note that the discovery of S/MARs has two major routes:

Subsequent work demonstrated both the constitutive (SAR-like) and the facultative (MAR-like) function of the elements depending on the context. Whereas constitutive S/MARs were found to be associated with a DNase I hypersensitive site in 'all' cell types (whether or not the enclosed domain was transcribed), DNAse I hypersensitivity of the facultative type depended on the transcriptional status. [4] The major difference between these two functional types of S/MARs is their size: the constitutive elements may extend over several kilobasepairs whereas facultative ones are at the lower size limit around 300 base pairs.

The figure shows our present understanding of these properties and it incorporates the following findings:

Use in gene therapy

As an alternative to viral vectors, which can have unwanted effects in patients body, non-viral methods of gene therapy are being studied. One of such methods uses plasmids with special properties - the so-called episomes. Episomes have the ability to divide together with the rest of eukaryotic genome during mitosis. Compared with standard plasmids they are not epigenetically silenced within nucleus and are not enzymatically destroyed. Episomes acquire this ability through the presence of S/MAR sequence within their construct. [7]

Additional information

In 2006, Tetko found a strong correlation of intragenic S/MARs with spatiotemporal expression of genes in Arabidopsis thaliana . [8] On a genome scale, pronounced tissue- and organ-specific and developmental expression patterns of S/MAR-containing genes have been detected. Notably, transcription factor genes contain a significant higher portion of S/MARs. The pronounced difference in expression characteristics of S/MAR-containing genes emphasizes their functional importance and the importance of structural chromosomal characteristics for gene regulation in plants as well as within other eukaryotes.

Related Research Articles

<span class="mw-page-title-main">Cell nucleus</span> Eukaryotic membrane-bounded organelle containing DNA

The cell nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm; and the nuclear matrix, a network within the nucleus that adds mechanical support.

Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.

<span class="mw-page-title-main">Euchromatin</span> Lightly packed form of chromatin that is enriched in genes

Euchromatin is a lightly packed form of chromatin that is enriched in genes, and is often under active transcription. Euchromatin stands in contrast to heterochromatin, which is tightly packed and less accessible for transcription. 92% of the human genome is euchromatic.

Heterochromatin is a tightly packed form of DNA or condensed DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role in the expression of genes. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002), and many other papers since, much of this DNA is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO4 staining reveal that the dense packing is not due to the chromatin.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<span class="mw-page-title-main">Nuclear lamina</span>

The nuclear lamina is a dense fibrillar network inside the nucleus of eukaryote cells. It is composed of intermediate filaments and membrane associated proteins. Besides providing mechanical support, the nuclear lamina regulates important cellular events such as DNA replication and cell division. Additionally, it participates in chromatin organization and it anchors the nuclear pore complexes embedded in the nuclear envelope.

<span class="mw-page-title-main">Constitutive heterochromatin</span>

Constitutive heterochromatin domains are regions of DNA found throughout the chromosomes of eukaryotes. The majority of constitutive heterochromatin is found at the pericentromeric regions of chromosomes, but is also found at the telomeres and throughout the chromosomes. In humans there is significantly more constitutive heterochromatin found on chromosomes 1, 9, 16, 19 and Y. Constitutive heterochromatin is composed mainly of high copy number tandem repeats known as satellite repeats, minisatellite and microsatellite repeats, and transposon repeats. In humans these regions account for about 200Mb or 6.5% of the total human genome, but their repeat composition makes them difficult to sequence, so only small regions have been sequenced.

In biology, the nuclear matrix is the network of fibres found throughout the inside of a cell nucleus after a specific method of chemical extraction. According to some it is somewhat analogous to the cell cytoskeleton. In contrast to the cytoskeleton, however, the nuclear matrix has been proposed to be a dynamic structure. Along with the nuclear lamina, it supposedly aids in organizing the genetic information within the cell.

HMGN proteins are members of the broader class of high mobility group (HMG) chromosomal proteins that are involved in regulation of transcription, replication, recombination, and DNA repair.

<span class="mw-page-title-main">Nuclear gene</span> Gene located in the cell nucleus of a eukaryote

A nuclear gene is a gene that has its DNA nucleotide sequence physically situated within the cell nucleus of a eukaryotic organism. This term is employed to differentiate nuclear genes, which are located in the cell nucleus, from genes that are found in mitochondria or chloroplasts. The vast majority of genes in eukaryotes are nuclear.

An insulator is a type of cis-regulatory element known as a long-range regulatory element. Found in multicellular eukaryotes and working over distances from the promoter element of the target gene, an insulator is typically 300 bp to 2000 bp in length. Insulators contain clustered binding sites for sequence specific DNA-binding proteins and mediate intra- and inter-chromosomal interactions.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">SAFB</span> Protein-coding gene in the species Homo sapiens

Scaffold attachment factor B, also known as SAFB, is a gene with homologs that have been studied in humans and mice.

<span class="mw-page-title-main">SATB1</span> Protein-coding gene in the species Homo sapiens

SATB1 is a protein which in humans is encoded by the SATB1 gene. It is a dimeric/tetrameric transcription factor with multiple DNA binding domains. SATB1 specifically binds to AT-rich DNA sequences with high unwinding propensity called base unpairing regions (BURs), containing matrix attachment regions (MARs).

<span class="mw-page-title-main">Inner nuclear membrane protein</span> Protein embedded in inner membrane of nuclear envelope

Inner nuclear membrane proteins are membrane proteins that are embedded in or associated with the inner membrane of the nuclear envelope. There are about 60 INM proteins, most of which are poorly characterized with respect to structure and function. Among the few well-characterized INM proteins are lamin B receptor (LBR), lamina-associated polypeptide 1 (LAP1), lamina-associated polypeptide-2 (LAP2), emerin and MAN1.

<span class="mw-page-title-main">Replication timing</span>

Replication timing refers to the order in which segments of DNA along the length of a chromosome are duplicated.

<span class="mw-page-title-main">DNase I hypersensitive site</span>

In genetics, DNase I hypersensitive sites (DHSs) are regions of chromatin that are sensitive to cleavage by the DNase I enzyme. In these specific regions of the genome, chromatin has lost its condensed structure, exposing the DNA and making it accessible. This raises the availability of DNA to degradation by enzymes, such as DNase I. These accessible chromatin zones are functionally related to transcriptional activity, since this remodeled state is necessary for the binding of proteins such as transcription factors.

<span class="mw-page-title-main">Nuclear organization</span> Spatial distribution of chromatin within a cell nucleus

Nuclear organization refers to the spatial distribution of chromatin within a cell nucleus. There are many different levels and scales of nuclear organisation. Chromatin is a higher order structure of DNA.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

<span class="mw-page-title-main">MNase-seq</span> Method used to analyse protein interactions with DNA

MNase-seq, short for micrococcal nuclease digestion with deep sequencing, is a molecular biological technique that was first pioneered in 2006 to measure nucleosome occupancy in the C. elegans genome, and was subsequently applied to the human genome in 2008. Though, the term ‘MNase-seq’ had not been coined until a year later, in 2009. Briefly, this technique relies on the use of the non-specific endo-exonuclease micrococcal nuclease, an enzyme derived from the bacteria Staphylococcus aureus, to bind and cleave protein-unbound regions of DNA on chromatin. DNA bound to histones or other chromatin-bound proteins may remain undigested. The uncut DNA is then purified from the proteins and sequenced through one or more of the various Next-Generation sequencing methods.

References

  1. ↑ "SMARtDB". Department of Bioinformatics. Göttingen, Germany: University of Göttingen.
  2. ↑ Mirkovitch J, Mirault ME, Laemmli UK (November 1984). "Organization of the higher-order chromatin loop: specific DNA attachment sites on nuclear scaffold". Cell. 39 (1): 223–232. doi:10.1016/0092-8674(84)90208-3. PMID   6091913. S2CID   24634819.
  3. ↑ Cockerill PN, Garrard WT (January 1986). "Chromosomal loop anchorage of the kappa immunoglobulin gene occurs next to the enhancer in a region containing topoisomerase II sites". Cell. 44 (2): 273–282. doi:10.1016/0092-8674(86)90761-0. PMID   3002631. S2CID   26202934.
  4. 1 2 Klar M, Stellamanns E, Ak P, Gluch A, Bode J (December 2005). "Dominant genomic structures: detection and potential signal functions in the interferon-beta domain". Gene. 364: 79–89. doi:10.1016/j.gene.2005.07.023. PMID   16185826.
  5. ↑ Heng HH, Goetze S, Ye CJ, Liu G, Stevens JB, Bremer SW, et al. (March 2004). "Chromatin loops are selectively anchored using scaffold/matrix-attachment regions". Journal of Cell Science. 117 (Pt 7): 999–1008. doi:10.1242/jcs.00976. PMID   14996931.
  6. ↑ Jackson DA, Dolle A, Robertson G, Cook PR (August 1992). "The attachments of chromatin loops to the nucleoskeleton". Cell Biology International Reports. 16 (8): 687–696. doi:10.1016/s0309-1651(05)80013-x. PMID   1446346.
  7. ↑ Mulia GE, Picanço-Castro V, Stavrou EF, Athanassiadou A, Figueiredo ML (October 2021). "Advances in the Development and the Applications of Nonviral, Episomal Vectors for Gene Therapy". Human Gene Therapy. 32 (19–20): 1076–1095. doi:10.1089/hum.2020.310. PMC   8819515 . PMID   34348480.
  8. ↑ Tetko IV, Haberer G, Rudd S, Meyers B, Mewes HW, Mayer KF (March 2006). "Spatiotemporal expression control correlates with intragenic scaffold matrix attachment regions (S/MARs) in Arabidopsis thaliana". PLOS Computational Biology. 2 (3): e21. doi: 10.1371/journal.pcbi.0020021 . PMC   1420657 . PMID   16604187.
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