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The evolution of mitochondrial genomes is an interesting field of biological study because the initial endosymbiosis event presents many challenges in gene expression, inheritance, and signalling to both precursor cells. Mitochondria were acquired as free-living prokaryotes for their ability to undergo aerobic respiration. Mitochondrial DNA (mtDNA) is now found in all eukaryotic cells - either in fully-functional mitochondria, or as a vestige in hydrogenosomes or mitosomes.

Mitochondrial genomes contain roughly similar numbers of genes between walks of life, but display a disproportionately wide variation in genome size. In animals including humans, the mitochondrial genome is around 15 kilobase pairs (kb) in size, whereas in plants, the number exceeds 200 kb in angiosperms and reaches 11 megabase pairs (Mb) in Silene. The disparity between genome size and gene number seems to be due to expansion of repeats and acquisition of sequences from other sources. Plant mtDNA contains very many direct and inverted repeats. Chromosome topology in mitochondria is traditionally thought to be a single circle, but there are reports suggesting linear, branched, and multiple minicircle genome organisations - particularly in plants.

Nuclear control is exerted on the mitochondrion at the level of transcription. The mitochondrial DNA-dependent RNA polymerase PolRmt contains two N-terminal pentatricopeptide repeats (PPRs), is T3/T7 phage-like, and is nuclear-encoded. With the help of transcription factors TFAM, TFB1M, and TFB2M, it initiates at three promoters: one light-strand promoter (LSP) and two heavy-strand promoters (HSP). The transcript from HSP1 is short, terminating at the end of the rRNA operon, whereas HSP2 transcribes the heavy strand almost completely. The transcript from LSP also contains primers for heavy strand replication. mTERFs 1-4 are involved in transcription termination, but only mTERF1 has been well characterised. Global transcription activity is controlled in the nucleus by the transcription factors NRF-1, NRF-2, and PGC-1.

Genes encoded on the mitochondrial genome have a propensity to migrate to the nucleus. Remarkably, such a migration event can be assayed in the lab. In a ura3 background, a construct containing the URA3 gene under the control of a nuclear promoter is inserted into the mitochondrial genome. While on mtDNA, the URA3 gene is not transcribed and the cell cannot grow without uracil. The migration event allows URA3 expression from the nuclear genome, rescues the ura phenotype, and allows the cell to grow without uracil.

Mitochondrial genes migrate into the nucleus to escape AT-richness, codon bias, mitochondrial gene regulation, and an asexual population (by Muller’s ratchet). The relative ease, as shown in the gene migration assay, for genes to do this may reflect a selective force in the direction of migration and endosymbiosis: the nucleus offers the above benefits, immortalises the mitochondrial genes into the nuclear genome, and ‘kills’ the mitochondrion by now making it dependent on the nucleus.

There still exist reasons why mitochondrial genes should remain in the mitochondrion. Retention allows local response to individual needs that is specific and rapid, including co-location for redox regulation (CORR). Retention may alternatively be forced because the protein product is difficult to import through a double membrane or because the limited transfer period has passed.

Retrograde signalling from the mitochondrion back to the nucleus is desirable so that the mitochondrion can report its health to the nucleus, and so that the nucleus can produce mitochondrial products in the correct stoichiometry and/or at the correct time - especially as some interacting partners in the mitochondrion are now encoded on the nuclear genome. A well-characterised example is nuclear CIT2 expression, which is regulated based on mitochondrial health. Underphosphorylated Rtg1/3 activates CIT2 expression by binding its R box on the upstream activating sequence (UAS). Rtg1/3 is inhibited from leaving the mitochondrion by phosphorylation on Rtg3 by Mks1. Mks1 is positively regulated by Bmh1/2 and 14-3-3 proteins, and negatively regulated by Grr1. Rtg3’s inhibitory phosphates are removed by Rtg2, which also dissociates Bmh1 from Bmh2. Rtg2 is negatively regulated by ATP, glutamate, glutamine, and TOR signalling, which are high when the mitochondrion is active. Thus, low mitochondrial activity is the signal stimulating nuclear CIT2 expression via Rtg1/3 and Rtg2.

Further reading:

Gualberto, J.M.; Mileshina, D.; Wallet, C.; Niazi, A.K.; Weber-Lotfi, F.; Dietrich, A. 2014. “The plant mitochondrial genome: Dynamics and maintenance.” Biochimie 100:107-120.

Falkenberg, M.; Larsson, N.-G.; Gustafsson, C.M. 2007. “DNA replication and transcription in mammalian mitochondria.” Annual Review of Biochemistry 76:679-699.

Thorsness, P.E.; Fox, T.D. 1990. “Escape of DNA from mitochondria to the nucleus in Saccharomyces cerevisiae.” Nature 346:376-379.

Liu, Z.; Butow, R.A. 2006. “Mitochondrial retrograde signaling.” Annual Review of Genetics 40:159-185.

Ayraethazide. 2015. “Transcription and Processing in Mitochondria.” [Accessed 2015-12-29.]

ayraethazide

My attempt at revising chloroplast genomes on New Year’s Eve and the birthday of meine Freundin. Chloroplast DNA (cpDNA) is like mitochondrial DNA (mtDNA) in that they are found in eukaryotes, originate from endosymbiosis event(s), migrate their genes to the nucleus, and display varying degrees of genome loss. Plastid genome architecture is less wildly variable than that of mitochondria, and plastids of secondary endosymbionts can harbour a fourth genome - the nucleomorph. Pentatricopeptide repeat (PPR) proteins are used extensively in plants and control aspects of gene expression regulation such as mRNA stability, splicing, editing, and translation. Immortalisation of the chloroplast into an endosymbiotic lifestyle requires retrograde signalling back to the nucleus through two to four membranes.

Fragmentation of the chloroplast genome is a rare event due to two large inverted repeats. Recombination across the repeats results in an inversion of the intervening sequence. Recombination across direct repeats results in fragmentation - and plant mtDNA is full of both direct and inverted repeats. Like mitochondria, some genes have migrated to the nucleus, with a core set of genes retained on the plastid genome for rapid and specific self-regulation. Dinoflagellates are extreme minimalists, encoding a small subset of these core genes on multiple minicircle choromosomes. Non-photosynthetic plants may lose photosynthetic genes but retain genes required for iron-sulphur cluster biosynthesis. Complete loss of cpDNA without loss of the compartment is reported in Polymotella and Rafflesia.

Primary endosymbionts which are taken up by another eukaryotic host have four genomes. The original nucleus degenerates into a nucleomorph, displaying massive gene loss. Convergent evolution is displayed between chloroarachniophytes and cryptophytes, suggesting a common selective pressure to migrate genes in this kind of secondary endosymbiont.

Genes on cpDNA are transcribed by two different polymerases: a nuclear-encoded polymerase (NEP), and a plastid-encoded polymerase (PEP). The NEP is phage-like but recognises bacterial-type -35 and -10 promoter sequences, while the PEP is bacterial-like and uses sigma-like factors for specificity. SIG1 responds to the PQ pool state while SIG2 is involved with circadian regulation. Six SIG proteins have been characterised.

Pentratricopeptide repeats (PPRs) are 35mers which recognise RNA nucleotides via two antiparallel helices. Residues 6 and 1’ (the first residue on the following PPR motif) determine the RNA-binding specificity - this is the PPR code. RNA binding by PPR proteins regulate expression by controlling mRNA stability (MCA1 on petA), splicing (PPR4), editing (CRP4), and translation (PPR10 on atpH).

Retrograde signalling back to the nucleus is for all the same reasons as why mitochondria need to do it. Perhaps the best-characterised example is the genomes-uncoupled (gun) mutants, which continue to send the signal to the nucleus to express CAB despite thylakoid loss.

Norflurazon inhibits carotenoid biosynthesis and leads to thylakoid loss. In a wild-type background, thylakoid loss causes decreased CAB expression from the nucleus. gun mutants express CAB even when norflurazon-treated. Six gun mutants have been characterised: gun1, which encodes a PPR protein thought to be in the tetrapyrrole biosynthesis pathway. gun2-5 encode tetrapyrrole metabolism proteins, while the gun6 mutant causes overexpression of ferrochetalase 1 (FC1), which produces haem. It is generally agreed that haem is the positive retrograde signal stimulating nuclear CAB expression and thereby attenuating the effect of thylakoid loss. Previously it was thought that Mg-protoporphyrin IX (Mg-PP) was a negative retrograde signal, as its levels were lowered in gun5 mutants.

Okay, time to stop working and celebrate. Happy New Year!

Actually, further reading:

Smith, D.R.; Keeling, P.J. 2015. “Mitochondrial and plastid genome architecture: Reoccurring themes, but significant differences at the extremes.” Proceedings of the National Academy of Sciences, USA. 112:10177-10184.

Tanifuji, G.; Onodera, N.T.; Brown, M.W.; Curtis, B.A.; Roger, A.J.; Wong, G.K.-S.; Melkonian, M.; Archibald, J.M. 2014. “Nucleomorph and plastid genome sequences of the chlorarachniophyte Lotharella oceanica: convergent reductive evolution and frequent recombination in nucleomorph-bearing algae.” BMC Genomics 15:374.

Zhelyazkova, P.; Sharma, C.M.; Förstner, K.U.; Liere, K.; Vogel, J.; Börner, T. 2012. “The primary transcriptome of barley chloroplasts: Numerous noncoding RNAs and the dominating role of the plastid-encoded RNA polymerase.” Plant Cell 24:123-136.

Barkan, A.; Small, I. 2014. “Pentatricopeptide repeat proteins in plants.” Annual Review of Plant Biology 65:415-442.

Beale, S.I. 2011. “Chloroplast signalling: Retrograde regulation revelations.” Current Biology 21 (10):R391-393.

Ayraethazide. 2015. “Transcription and Translation in Chloroplasts.”

ayraethazide

An epigenetic histone modification associated with heterochromatic state of nuclear chromatin is methyl-lysine 9 on histone H3 (H3K9Me). Certain proteins can recognise dimethyl-lysine via their chromodomains and recruit effectors to the chromatin via their shadow chromodomains. Heterochromatin protein 1 (HP1), known as mouse chromatin modifier protein 1 (MoMOD1) in mice and Swi6 in yeast, is one such protein, and is thought to cause the heterochromatic state through compaction of polynucleosomes and recruitment of interacting partners. Genes within heterochromatin are repressed - this is a gene expression regulation feature that is unique to eukaryotes.

Structure and sequence

Chromodomains and shadow chromodomains resemble each other in structure and sequence. They form an N-terminal three-strand antiparallel β-sheet overlaid by C-terminal α-helix. In shadow chromodomains, the residues I161, Y164, and W170 show elevated levels of conservation compared to the equivalent positions in the chromodomain - this is probably due to retain the dimerisation function of the C-terminal region, where those residues lie.

One monomer of HP1 contains an N-terminal chromodomain and a C-terminal shadow chromodomain. HP1 exists in vivo as a homodimer. This means that one homodimer of HP1 contains two chromodomains and two shadow chromodomains. The dimerisation interface is between the two shadow chromodomains at the unstructured C-terminus and α-helix. N-termini are also unstructured, which gives the overall structure a high degree of structural flexibility.

Interaction of the shadow chromodomain

Through a variety of GST-pulldown assays and LexA/VP16 two-hybrid assays of MoMOD1 with CAF-1, the minimal interacting region (MIR) was identified. This contains the motif PxVxL. NMR structural studies show that proteins bearing the PxVxL bind HP1 at the dimerisation interface between the two shadow chromodomains - explaining why monomers of MoMOD1 did not display binding with CAF-1. Binding creates an unorthadox three-standed β-sheet with the unstructured C-terminal regions on each of the shadow chromodomains; formally, it is two separate β-sheets: one parallel, and one antiparallel.

Interaction of the chromodomain

Structural insight elucidated that the all-important H3K9Me2 epigenetic mark is bound by a hydrophobic groove in the chromodomain through a combination of hydrophobic and π aromatic interactions. Mutation at Y21, W42, or F45 reduce these interactions. Binding is specific to substrates with the tetrapeptide Q5, A7, R8, K9 - histone H3 has QTARK. Mutation in this region extinguishes binding of chromodomain substrates.

Compaction of chromatin

HP1 dimerises via shadow chromodomains. HP1 dimers therefore have two chromodomains, which can each bind a different H3K9Me2 mark on two different nucleosomes. Each nucleosome has two H3 histones, and if one HP1 dimer binds only once to a single nucleosome, then this gives a mechanism for heterochromatin spreading by ‘sticky ends’. Swi6 has been shown to bind longer polynucleosomes with greater specificity than shorter polynucleosomes. In 1N and 2N stretches, Swi6 bound nonspecifically to linker DNA and not histone H3. HP1 binding the same nucleosome twice is futile and is not compatible with the sticky end mechanism.

Further reading:

Ball, L.J.; Murzina, N.V.; Broadhurst, R.W.; Raine, A.R.C.; Archer, S.J.; Stott, F.J.; Murzin, A.G.; Singh, P.B.; Domaille, P.J.; Laue, E.D. 1997. “Structure of the chromatin binding (chromo) domain from mouse modifier protein 1.” EMBO Journal 16:2473-2481.

Smothers, J.F.; Henikoff, S. 2000. “The HP1 chromo shadow domain binds a consensus peptide pentamer.” Current Biology 10:27-30.

Thiru, A.; Nietlispach, D.; Mott, H.R.; Okuwaki, M.; Lyon, D.; Nielsen, P.R.; Hirshberg, M.; Verreault, A.; Murzina, N.V.; Laue, E.D. 2004. “Structural basis of HP1/PXVXL motif peptide interactions and HP1 localisation to heterochromatin.” EMBO Journal 23:489-499.

Nielsen, P.R.; Nietlispach, D.; Mott, H.R.; Callaghan, J.; Bannister, A.; Kouzarides, T.; Murzin, A.G.; Murzina, N.; Laue, E.D. 2002. “Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9.” Nature 416:103-107.

Canzio, D.; Chang, E.Y.; Shankar, S.; Kuchenbecker, K.M.; Simon, M.D.; Madhani, H.D.; Narlikar, G.J.; Al-Sady, B. 2011. “Chromodomain-mediated oligomerization of HP1 suggests a nucleosome-bridging mechanism for heterochromatin assembly.” Molecular Cell 47:67-81.

archenland

SEM pictures of Emiliania huxleyi cells

It is one of thousands of different photosynthetic plankton that freely drift in the euphotic zone of the ocean, forming the basis of virtually all marine food webs.

Seeing many girls who look underage...

I am seeing way too many girls who look underage writing about being submissives to "Daddy" I am worried that some old fart pedophiles are using children for their sick desires. Doesn't anyone monitor this site? Doesn't anyone care that these girls could be victims and need help?

I always thought that my dream of helping people at a beautiful retreat, was just that a Dream. "I will never have the money I thought"-so I put it on the back burner of my mind, and just kept seeing myself as a healer to couples once so often, sitting in a room with people doing a workshop, with a smile on my face, so genuinely happy. Internet these days and networking with thousands of people, makes things possible. I got that sparkle of hope in my eyes again. So I am going for it and I hope that you are all behind me and will cheer me on. I already have a few ney say sayers. I will not give up. Please, pretty please, with honey on top and sweet hugs, if you have any contacts who may be interested in investing in a "woman owned business" please help us connect. I will never get this done on my own, well maybe I will but a little help from my friends will make it happen a LOT faster and smoother. I Love you <3 Dr. Grace https://www.facebook.com/valhallaislandcouplesretreat

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sciteachers

I haven’t posted much recently because I had much school stuff to do. As an apology, I offer you this gif of a tardigrade (water bear) snoodling up its food:

(5 Reasons Why the Tardigrade is Nature’s Toughest Animal)

23pairsofchromosomes

These little guys sure are hardy little creatures, but there are some other microorganisms out there that beat these little guys hands down.

Second Opinion: Laetrile At Sloan-Kettering (Full Package) on VHX

With all the poison, pesticides, gmo's and toxins in our foods, and our foods being void of nutrients we need, because of these substances being present, more than ever, people are getting cancer. Even people and children, who's family have no history of cancer.

ayraethazide

How to remember the single-letter amino acid code

The three-letter amino acid code is easy. They are largely predictable (like the first three letters) and are unambiguous. Maybe, maybe, Ile (isoleucine) and Sec (selenocysteine) will cause a little trouble, but it’s not hard to get over. Now, inspired by a recent biochemistry lecture, and as a follow-up for the renewed amino acid infographic I posted earlier today, here are some ways to remember the single-letter code.

It’s the first letter of most amino acids. Alanine, Cysteine, Glycine, Histidine, Isoleucine, Leucine, Methionine, Proline, Serine, Threonine, Valine.

It’s phonetic for some amino acids. Feenylalanine, aRginine, tYrosine.

For a few, it’s phonetic when you say it weirdly. AsparDate, glutEmic ecid, asparagiNe, Qutamine, sUhlenocysteine, tWyptowphan.

And finally, it makes more sense when you make a typo. KLysine.

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