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Experimental perturbations to investigate cardiovascular physiology
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
Recently, a new technique to edit the genome has been adapted making use of the clustered regularly interspaced short palindromic repeats (CRISPR) system. In bacteria, this system allows short sequences of viral DNA known as spacer DNA to be inserted into the genome (between the short palindromic base sequences), recording over time which viruses the bacteria have been exposed to. The spacer sequences help the CRISPR-associated system (Cas) proteins identify and cut similar DNA from infecting viruses or plasmids, allowing a future adaptive immune response to be generated against them. In 2012, the Doudna and Charpentier groups described how a simple CRISPR/ Cas9 system could be used along with synthetic guide RNA (gRNA) to cut, remove or edit cellular genomic DNA. Then, in 2013, the Zhang and Church groups described genome editing with the CRISPR/Cas9 technique in human cell cultures.
Role of Histones in Cell Differentiation
Published in Gerald M. Kolodny, Eukaryotic Gene Regulation, 2018
Another mechanism involved in higher-order chromatin organization may be a process of self-assembly of identical nucleosomes into knobs or solenoid structures246 which are additionally stabilized by H1 crosslinking. The supercoiling of DNA in the nucleosomes may favor especially the binding of H1 which was shown to exhibit a large preference for superhelical DNA.247 Another possibility for a strong stabilization of nucleosomal supercoils is the binding of some nonhistone proteins as suggested by protein A24 representing a covalently linked complex of a nonhistone protein and H2a.248 More recent data suggest the interesting possibility that the N-terminal ends of the nucleosomal histones are responsible for the interaction of the spacer DNA with the nucleosomes, thus providing a mechanism for their tight packing.148b
Chromatin Structure and Gene Regulation
Published in M. Gerald, M.D. Kolodny, Eukaryotic Gene Regulation, 2018
Although spacer DNA is preferentially attacked by nucleases, the nucleosome core is also digested at a much slower rate.3,123 It is evident from studies with DNAse I that there are discrete cleavage sites within the nucleosome such that cutting sites display a 10 base pair periodicity. The 140 base pairs comprising the core are most frequently attacked at sites corresponding to 10, 20, 40, 50, 90, 100, 120, and 130 base pairs. Nucleosome end labeling experiments have shown that sites at 30, 80, and 110 are quite insensitive to digestion. 105,126,155 Clearly the digestion patterns reflect a precise arrangement of histones among themselves and in association with DNA within the nucleosome. Several models have been put forward to explain the findings in terms of the DNA configuration within the nucleosome. The reader is referred to a recent review by Felsenfeld51 for more details.
Developments in lncRNA drug discovery: where are we heading?
Published in Expert Opinion on Drug Discovery, 2018
Ilya Blokhin, Olga Khorkova, Jane Hsiao, Claes Wahlestedt
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 machinery is yet another non-coding RNA-based mechanism that evolved in bacteria as a defense against viruses. Structurally, bacterial CRISPR consists of spacers (short remnants of genetic code from past bacteriophage invaders) interspersed with repetitive sequences. When a bacterium is invaded by a phage or plasmid for the first time, foreign DNA is degraded and its fragments are inserted into CRISPR regions, forming new spacers. In response to subsequent infections with the same DNA, spacer DNA is transcribed into short RNAs (CRISPR RNAs or crRNAs) which, in association with the Cas9 endonuclease, target and degrade complementary viral DNA. This mechanism, known since 2005, has been employed to introduce immunity against phages into bacteria of industrial importance. In 2012, CRISPR-Cas9 system was successfully used for sequence-specific genome editing [11] which subsequently led to extensive translational efforts.