Nuclear matrices or nuclear scaffold were defined by biochemical fraction of nucleus after treatment by with detergent, salt and nucleases. They mainly consist of nonhistone protein, RNA and DNA in eukaryote.
Chromatin is looped into domains by attachment of chromatin fibre to nuclear matrix.
DNA sequences that bind preferentially nuclear matrices are matrix attachment region (MAR) or scaffold associated region (SAR). MARs are 200bp long, AT-rich, contain topoisomerase II consensus sequences and other AT-rich sequence motifs. They are near cis-acting regulatory sequences. Their binding sites are abundant.
They are enriched in inverted repeats, AT tracts, DNA unwinding elements, replication initiator protein sites, homooligonecleotide repeats, etc.
Many known MARs do not have extensive sequence homology. They appear to be functionally conserved. Animal MARs can bind plant nuclear scaffolds and vice versa.
Role of nuclear organisation in cancer
Nuclear matrix proteins involved in regulating gene expression, DNA replication and repair. Chromatin folding facilitates interactions between genomic regions to enable or repress transcription. It enables individual genomic regions to be insulted from surrounding regions. Nuclear matrix proteins are aberrantly expressed in cancer.
Nuclear matrix proteins as cancer markers
Proteins aberrantly expressed in spec forms of cancer can be used to improve diagnosis.
Generation of chromosome rearrangements
2 models for translocation in cancer.
In breakage first model, genomic regions containing double stranded breaks move in nucleus. They can illegitimately recombine with other genomic regions with DSBs.
In contact first model, local recombination events arise at DSBs in chromosomes already proximally positioned. Contact-first model appears to be correct.
Gene fusions caused by translocations in cancer cells correlates with frequency of side by side pairing of genes in normal control cells.
Replication and transcription: shaping landscape of genome by Chakalova et al
The proteomes of trascnription factories containing RNA polymerases I, II and III by Melnik et la
|(a) Numbers of proteins in the different complexes and their overlap. (b) Many proteins in each complex are associated with the GO term 'gene expression' (GO: 0010467), and complex II contains more with 'transcription from RNA polymerase II promoter' (GO: 0006366) than do complexes I and III. (c) Most proteins in each complex possess GO terms related to transcript production. Selected GO terms were incorporated into eight groups; for example, 'transcription' includes terms 'RNA polymerase', 'transcription factor' and 'transcription regulation'), and 'other terms' includes those not in the other seven groups. Four additional sets of proteins are included for comparison on the right. Some proteins possess terms in more than one group, and terms in each group are expressed as a fraction of the total in all groups. In each complex, 2% of proteins lacked any GO term, and many proteins in the complexes associated with 'other terms' nevertheless turn out to have a role in transcript production (for example, actin21 proteasomal constituents17 and nucleoporins22). Each complex has a characteristic pattern, which is distinct from those given by proteins with the terms 'cytoplasm' and 'S100'|
Replication and transcription: shaping the landscape of the genome
Mouse haemoglobin β-chain complex (Hbb) genes and their distal regulatory elements, locus control region (LCR) more than 50kb away engage and specific higher order, loop structures during transcription.
Only 1 out ot 9 distal regulatory elements clustering around active Hbb gene is known to be a classical enhancer. Other sequence elements have insulator like properties, intergenic promoter activity. They coalesce into an active chromatin hub.
|A hub that is formed by long-range interactions between the haemoglobin -chain complex (Hbb) genes and the locus control region is shown. Transcriptional activation involves physical association of genes and their regulatory elements. This arrangement could increase the local concentration of trans-acting transcription factors by spatial clustering of binding sites for such factors95, 96, 105. The coloured circles represent DNaseI hypersensitive sites.|
Different genes often co-occupy the same factory. This indicates that genes do not assemble their own transcription sites de novo when the become active. They migrate to preassembled transcription site.
Studies indicate that transcription factories assemble on a scaffold or nuclear matrix. A stab;e factory implies that genes of transcription units would be pulled though a factory rather than pols moving along chromatin fibre.
Prokaryotic RNAP is a powerful motor protein. Tractor forces from efficient conversion of free energy due to nucleotide hydrolysis during intergenic transcript elongation could ratchet distal regulatory elements and target genes into a common factory. This facilitates formation of long range cis interactions.