Meet Genetic master chefs [Trans fac]

Generic master chefsʼ recipes for life

• Fruit fly/nematode worm (well-mapped mlc genetics):
• Research in gene expression progressing at a hectic pace
• (Mammals = early days)
• [hope human genome project --> mlc genetics of mammals --> assult on trans fac]
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• Cancer --> turned on (uncontrolled) cell growth
• HIV --> own trans facs --> take over
• CVD(partly)- harmful turned on
• --> research ctrl gene expression e.g. antiviral to inactivate trans fac

Gene Ctrl
• Gene therapy (healthy genes) + Trans fac to ctrl expression --> overide effects of damaged genes
• Current: Understanding basic Sci of trans fac
• (“supposed to be enormously scarce” [referring to older studies on bacteria] )
• Current estimate: 1000 < x < 10,000 / 100,000 (total no. of genes)
• conc. = up to 20,000 mlc / cell
• Collaborate --> ∞ combo ---> why genes can be “interpreted” in so many ways
• 1960s- transcription, translation
• RNA polymerase bind to “promoter”
• **[region of gene which protein binds causing assembling of mRNA]
• Postulate: RNA polymerase regulated by special protein subunits (“sigma factors”)
• join before transcription
• 1980s- proteins help RNA polymerase & activate specific genes
• SP1 in human cells- Tijan
• TFIIIA in frogsʼ eggs- Roeder, Rockefeller
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• Now: discovered +100 trans fac in yeast, mammals w/ similar functions

• Defining charac
• “DNA-binding domains”- recognise specific sequence, dock into grove btw 2 nucleotides
• Shapes- X-ray crystallography, NMR
• Similar shapes --> families: leucine zippers, helix-loop-helix, Zn fingers
• Leucine zipper- example of how trans facs can collaborate (---> ++combo)
• Most studied- “fos” and “jun” --> cell division
• implicated to cancer
• each = ½zip (∴ 2 = full zip)
• teeth = string of leucine amino (3 combo)
• 3 shapes of teeth from 3 combo- fos/fos jun/jun fos/jun
--> 3 diff. pathways
• ∴ Understanding “activation domain” (part of mlc where trans facs interact) is as
important as DNA-binding sequence

Activators and Repressors

• Overall shape is the most important
• Repressor [1990s] discovered protein in bacteriophages
• preventing RNA poly moving along it
• Blocking construction of DNA-binding complex
• Interfering w/ binding to DNA
• **“duke it out” = fight it out
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• Fruit flies embryos: “Dorsal” (trans fac)
• Different levels --> either development of muscles / internal organs / skin / nervous tissues
• ∴Different levels switch on diff. sets of genes
• Mech: interact w/ 2 other trans fac
• --> 3 different binding sites on DNA
• (on/off α spacing btw sites & presence of other trans facs)
• Behaving receptors for hormones (binding --> change role)
• e.g. to thyroid
• Test tube & culture studies: thyroid receptors --> off certain growth-related genes
• Part-time trans fac
• NF-k B
• usu. job = role in inflammation and immunity
• cell fluid, tethered to a 2nd protein
• bond occasionally break --> enters cell nucleus

Working together
• Way genes are packaged influences transcription
• Nucleosomes: DNA wrap around histones (large globular proteins)
• Other proteins: Stabilise the DNA & build up chromosome
• interactions w/ proteins --> some genes more accessible
• e.g. methylation = shield against transcription -> “genomic imprinting”
• **Genomic imprinting: The phenomenon of parent-of-origin gene expression. The expression of a gene depends upon the parent
who passed on the gene. [Wiki- Imprinted alleles are silenced, gene expressed from the allele given by the other parent]

• Some help chemical communications btw complex of trans facs, RNA poly and DNA
• Up to 60 proteins working together to turn on a single gene

• Donʼt need to understand mech of all [diff. mech but same biological response e.g. diff. pathways resulting
the same thing like inflammation]
• [Medical app- interfering w/ a single trans fac --> no bio response]
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• Q. from Medical app: Which one have greatest impact?
• Cracked gene expression in 10-15 years --> better picks

• (answers intellectual qs. along the way) e.g. Have trans facs become increasingly important w/ the evo
of complex organisms?
• “if %of trans fac in higher org more than lower org = same computer, more complex software”

• (1980s) Diverse species (Corn-yeast-humans) have similar stretches of DNA. “homeoboxes”

• (180 base-pairs coding for DNA-binding domains)
• Found in genes that ctrl construction of basic body plan of fruit flies
• (Now know) Genes that contain them encode a v. large class of trans fac (homeodomain trans fac)
• Regulate clusters along the chromosome in a sequence that corresponds to the order - from
head to tail (referring to chromosome) - of the body parts whose development they ctrl
• Genetic diseases- some leukaemia and syndromes that affect nervous system development linked to
defects in homeodomain trans facs
• --> mice studies

• เพ้อ (Eng: waffly)