Short and Sweet

Yamanaka strikes again. Citrulline is deiminated arginine, replacing a C=N-H (the imine) by a carbonyl C=O. An enzyme called PAD4 does the job. Why is it important? Because one of its targets is the H1 histone which links nucleosomes together. Recall that the total length of DNA in each and every one of our cells is 3 METERS. By wrapping the double helix around nucleosomes, the DNA is shortened by one order of magnitude.

So what? Well, at physiologic pH the imine probably binds another proton making it positively charged, making it bind to the negatively charged DNA phosphate backbone. Removing the imine makes this less likely to happen, so the linker doesn’t bind the double helix as tightly.

Duck soup for the chemist, but apparently no one had thought to look at this before.

This opens up the DNA (aka chromatin decondensation) for protein transcription. Why is Yamanaka involved? Because PAD4 is induced during cellular reprogramming to induced pluripotent stem cells (iPSCs), activating the expression of key stem cell genes. Inhibition of PAD4 lowers the percentage of pluripotent stem cells, reducing reprogramming efficiency. The paper is Nature vol. 507 pp. 104 – 108 ’14.

Will this may be nice for forming iPSCs, it should be noted that PAD4 is unregulated in a variety of tumors.

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  • Bryan  On March 11, 2014 at 7:22 pm

    Although it makes intuitive sense from the chemical point of view that histone modifications could directly affect the stability of histone-DNA interactions, in many cases that direct effect on nucleosome stability is not physiologically relevant. For example, converting a positively charged lysine into a neutrally charged residue through acetylation might be expected to directly loosen the structure of chromatin, but acetylating histones in vitro makes nucleosomal DNA only slightly more accessible (enough for the biophysicists to measure, but apparently not enough for the it to matter to the cell). Rather, histone tail acetylation leads to the opening of chromatin structures via the recruitment of bromo-domain containing proteins (such as the SWI/SNF and RSC chromatin remodeling complexes) associated with transcriptional activation and by inhibiting the recruitment of proteins associated with silencing (such as the ISWI chromatin remodeling complexes). Similarly, citrullination of H1 may not directly inhibit H1 binding and may instead act to recruit other factors involved in regulating chromatin structure. There is certainly the potential for a lot more to be discovered in following up on these results.

  • luysii  On March 11, 2014 at 8:40 pm

    Quite true, but the bromodomain is binding to something e.g. acetyl-lysine (and using something fairly complicated — a 110 amino acid left-handed bundle of 4 alpha helices forming a hydrophobic cavity with an asparagine at the base — to do so. The substituted urea moiety of citrulline, is sufficiently unusual that there may be a whole bunch of proteins binding to it, as you note. It would be interesting to use it as ‘bait’ to try and find them.

    The cell nucleus is really remarkable when you think about what is going on inside. I started writing a series of post about the cell nucleus on a human scale and got up to installment VI or so — I really should finish it. Here’s a link to the first one in the series — They are all in the category of the same name found to the left of the text.

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