Showing posts tagged epigenetics
SICK PAPES SPECIAL ON CONTROVERSY: PART 1
Hödl, M., & Basler, K. (2012). Transcription in the absence of histone H3.2 and H3K4 methylation. Current biology : CB, 22(23), 2253–2257. doi:10.1016/j.cub.2012.10.008
VERSUS
Pengelly, A. R., Copur, Ö., Jäckle, H., Herzig, A., & Müller, J. (2013). A histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. Science (New York, NY), 339(6120), 698–699. doi:10.1126/science.1231382
Biology is bursting at the seams with controversy. By far the most important controversy in modern biology is whether taking steroids makes your penis smaller, or whether this is just some D.A.R.E. bullshit they told us as kids to prevent us from fully achieving the glorious manifestation of our god-granted, muscly-man physiques. For those of us who believe that, in fact, steroids may help the enlarge the penis, a sub-controversy exists over whether one should inject the steroids directly into his or her penis. (Answer: currently up for debate on numerous message-boards.) Our colleagues have recently dubbed this expanding field “Penomics,” and we believe it to be rife with promise.
Arguably the SECOND-most important controversy in modern science is related to the importance of histone modifications in gene regulation and epigenetic inheritance. Here’s the low-down: DNA is a linear molecule, but is physically wrapped around structures made of histone proteins (the entire group of histones is collectively known as a “nucleosome”). The histone proteins can be modified at specific amino acids by the addition or removal of chemical groups such as methyl-, or acetyl-, which may help them physically move so that a given piece of DNA is “unwrapped” from the nucleosome and becomes relatively available for transcription.  
While there is undoubtedly a strong correlation between histone modification and transcriptional activity, skeptics have pointed out that there remains very little definitive proof that histone modifications are causally important for the regulation of the nearby DNA (i.e. whether a gene is “turned on” or not is influenced by the modifications on the nearby histones). Despite this uncertainty, many writers have gone way overboard and claimed that histone modifications represent the ultimate secret key by which gene regulation is maintained across multiple generations.  The masturbatory frenzy of celebration around this field has recently been strongly criticized by the God-like Mark Ptashne in a blunt letter he wrote to the Proceedings of the National Academy of Sciences.
The reason that there is so little direct evidence for the function of histone modification function is because histone proteins are exceedingly difficult to alter in vivo. This is because there are 23 copies of the histone genes (in fruit flies). What are you crazy sons-of-bitches gonna do, mutate ALL of them at once? In fact, yes. Some ambitious lads and lasses took advantage of the fact that these 23 histone genes all lie physically next to each other on the chromosome, and they built a fly with a large chromosomal deletion spanning this entire region. Then, by adding in mutant histone proteins (which, for example, cannot be chemically modified at a specific amino acid), they can ask whether this specific amino acid modification is actually necessary for the histone function.
These two papes present very similar experiments, but report essentially opposite conclusions (sort of). In Pape 1, dudes make a fly whose entire complement of Histone3 cannot be methylated at Lysine #4 (which has been proposed to be required for active transcription at a given genomic site) - i.e. every single nucleosome along the entire genome of a given cell contains histone3 that can’t be methylated at this position at all - and yet they find that these cells can transcribe perfectly fine, and express all the right genes.  In other words, methylation at H3K4 cannot be causally required for transcription. Ooh chi wally wally!
But then Pape 2 (Pig in the City) chimes in with a very similar fly, but whose Histone3 cannot be methylated at lysine #27 (another site proposed to be essential, this time for repressing genes). In these motherfucking flies, the cells have completely screwed up gene expression, exactly mimicking the effect of removing the methyl transferase that adds that methyl group. Ooh chi bang bang!!
The debate rages, dudes are battening down the hatches, and our blood-soaked tax dollars continue to fuel this Amazing Race. Me personally, if I have to take sides, I bet that histone modifications are causally important, but this feeling is entirely uninformed, its just my personality!!! 

SICK PAPES SPECIAL ON CONTROVERSY: PART 1

Hödl, M., & Basler, K. (2012). Transcription in the absence of histone H3.2 and H3K4 methylation. Current biology : CB, 22(23), 2253–2257. doi:10.1016/j.cub.2012.10.008

VERSUS

Pengelly, A. R., Copur, Ö., Jäckle, H., Herzig, A., & Müller, J. (2013). A histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. Science (New York, NY), 339(6120), 698–699. doi:10.1126/science.1231382

Biology is bursting at the seams with controversy. By far the most important controversy in modern biology is whether taking steroids makes your penis smaller, or whether this is just some D.A.R.E. bullshit they told us as kids to prevent us from fully achieving the glorious manifestation of our god-granted, muscly-man physiques. For those of us who believe that, in fact, steroids may help the enlarge the penis, a sub-controversy exists over whether one should inject the steroids directly into his or her penis. (Answer: currently up for debate on numerous message-boards.) Our colleagues have recently dubbed this expanding field “Penomics,” and we believe it to be rife with promise.

Arguably the SECOND-most important controversy in modern science is related to the importance of histone modifications in gene regulation and epigenetic inheritance. Here’s the low-down: DNA is a linear molecule, but is physically wrapped around structures made of histone proteins (the entire group of histones is collectively known as a “nucleosome”). The histone proteins can be modified at specific amino acids by the addition or removal of chemical groups such as methyl-, or acetyl-, which may help them physically move so that a given piece of DNA is “unwrapped” from the nucleosome and becomes relatively available for transcription.  

While there is undoubtedly a strong correlation between histone modification and transcriptional activity, skeptics have pointed out that there remains very little definitive proof that histone modifications are causally important for the regulation of the nearby DNA (i.e. whether a gene is “turned on” or not is influenced by the modifications on the nearby histones). Despite this uncertainty, many writers have gone way overboard and claimed that histone modifications represent the ultimate secret key by which gene regulation is maintained across multiple generations.  The masturbatory frenzy of celebration around this field has recently been strongly criticized by the God-like Mark Ptashne in a blunt letter he wrote to the Proceedings of the National Academy of Sciences.

The reason that there is so little direct evidence for the function of histone modification function is because histone proteins are exceedingly difficult to alter in vivo. This is because there are 23 copies of the histone genes (in fruit flies). What are you crazy sons-of-bitches gonna do, mutate ALL of them at once? In fact, yes. Some ambitious lads and lasses took advantage of the fact that these 23 histone genes all lie physically next to each other on the chromosome, and they built a fly with a large chromosomal deletion spanning this entire region. Then, by adding in mutant histone proteins (which, for example, cannot be chemically modified at a specific amino acid), they can ask whether this specific amino acid modification is actually necessary for the histone function.

These two papes present very similar experiments, but report essentially opposite conclusions (sort of). In Pape 1, dudes make a fly whose entire complement of Histone3 cannot be methylated at Lysine #4 (which has been proposed to be required for active transcription at a given genomic site) - i.e. every single nucleosome along the entire genome of a given cell contains histone3 that can’t be methylated at this position at all - and yet they find that these cells can transcribe perfectly fine, and express all the right genes.  In other words, methylation at H3K4 cannot be causally required for transcription. Ooh chi wally wally!

But then Pape 2 (Pig in the City) chimes in with a very similar fly, but whose Histone3 cannot be methylated at lysine #27 (another site proposed to be essential, this time for repressing genes). In these motherfucking flies, the cells have completely screwed up gene expression, exactly mimicking the effect of removing the methyl transferase that adds that methyl group. Ooh chi bang bang!!

The debate rages, dudes are battening down the hatches, and our blood-soaked tax dollars continue to fuel this Amazing Race. Me personally, if I have to take sides, I bet that histone modifications are causally important, but this feeling is entirely uninformed, its just my personality!!! 

Contributed by benewencampen
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