Genome complexity: controlling cell specificity (Introduction)

by David Turell @, Tuesday, August 22, 2017, 22:30 (518 days ago) @ David Turell

All cells have the same starting DNA with an allele from each parent, but not all alleles are expressed in different tissues. "Enhancer" areas in the DNA exert controls over the process of developing different functional tissues:

"Every gene in (almost) every cell of the body is present in two variants -- so called alleles: one is deriving from the mother, the other one from the father. In most cases both alleles are active and transcribed by the cells into an RNA message. However, for a few genes, only one allele is expressed, while the other one is silenced. The decision whether the maternal or the paternal version is shut down occurs early in embryonic development -- one reason, why for long it was thought that the pattern of active alleles is nearly homogeneous in the various tissues of the organism.

"The new study (DOI:10.7554/eLife.25125), where CeMM PhD Student Daniel Andergassen is first author, uncovers a different picture. By performing the first comprehensive analysis of all active alleles in 23 different tissues and developmental stages of mice, the team of scientists revealed that each tissue showed a specific distribution of active alleles.


"The scientists found that both genetic and epigenetic differences between the maternal and paternal allele contributed to the observed tissue-specific activity patterns. "Our results indicate that a large part of those patterns are induced by so-called 'enhancers'," co-senior author Quanah Hudson, now at IMBA (Institute for molecular Biotechnology of the Austrian Academy of Sciences) explains. "Enhancers are DNA regions that are often located at quite some distance from the observed allele, but nevertheless have a direct influence on their activity."

"'This study reveals for the first time a comprehensive picture of all active alleles in different tissues -- we have uncovered the first complete allelome" Florian Pauler, now at ISTA (Institute of Science and Technology Austria) and co-senior author, adds.


"Some of the genes that contributed to the tissue-specific activity patterns were located on the X chromosome and escaped so-called "X-chromosome inactivation," where one of the two X chromosomes in females gets shut down. Previously it was reported that around 3% of X-chromosomal genes in mice and 15% in humans escape inactivation. However, this study revealed that mice are more similar to humans than previously thought, with an average of around 10% of active genes escaping X-inactivation per tissue. By examining a broad range of organs the researchers showed that the number of escapers varies dramatically between tissues.


"Finally, the allelome offers a near complete picture of "genomic imprinting," the process that leads to epigenetic silencing of either the maternal or paternal allele that is initiated by an epigenetic mark placed in either the egg or sperm. Previously, it was reported that approximately 100 genes can be subject to imprinted silencing -- but in many cases, the tissue specificity was not known. This study led to the discovery of 18 new imprinted genes, validated some known genes and resolved the disputed status of some others to provide a gold standard list of 93 imprinted genes in mouse. The scientists found that those new genes were located near to other imprinted genes, indicating that they were co -- regulated. Interestingly, this study demonstrated that Igfr2, the first imprinted gene discovered by Denise Barlow in 1991, is surrounding by a large cluster of imprinted genes that extend over 10% of the chromosome, making it the largest co-regulated domain in the genome outside of the X chromosome. Fittingly, after her lab found the first imprinted gene, and discovered the first imprinted non-coding RNA shown to control imprinted silencing."

Comment: DNA doesn't just make protein. It has to use these complex arrangements to specify cells and tissues in production. This is specified complexity, which cannot have happened by chance.

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