Histone Methylation Determines Cell Fate
Gene expression is controlled at all sorts of levels in eukaryotic cells, and one of the hot areas is that of histone modifications and how they influence transcriptional accessibility on chromosomes - epigenetic regulation, as it’s called. Think of it as an analog annotation system for the cell’s genome, where each gene is wrapped up in such a way that it’s either accessible to transcriptional machinery or not. There are enzymes that add these annotations, and enzymes that remove them, which determine cell fate on one level in a sort of gene expression balancing act.
We call this mode of annotation “(de)methylation.” In histones and DNA itself, this type of modification appears to explain the problems that researchers have had in explaining certain aspects of pluripotency and cell differentiation, and the developmental defects following cloning by somatic cell nuclear transfer. It seems to explain how nuclei “remember” their previous cell state, and some euphemisms have come into use to collectively describe epigenetic mechanisms, such as “cell memory.”
DNA is packaged within the cell’s nucleus through its interaction with histone proteins (H2A, H2B, H3, and H4), which forms chromosomal regions that are either permissive or repressive for gene expression. Methylation of histones controls transcription by allowing chromosomal regions to toggle between “on” and “off ” states. Moreover, this modification is reversible.
In somatic cell nuclear transfer, the nucleus of a somatic cell from an adult individual is transplanted into an oocyte from which the nucleus has been removed, resulting in reprogramming of the adult nucleus and therefore successful development of the cloned animal. Cloning, however, has been inefficient to date, because of epigenetic defects, thought to be particularly due to varying methylation states.
Two papers published in last Friday’s Science cast some additional light on this problem, and are commented on in the perspective Unlocking Cell Fate. The two papers that Rivenbark and Strahl describe, Lee et al. and Chang et al. focus on H3K27 methylation states in particular:
H3K27 di- and trimethylation typically localize to the promoter region of developmentally regulated genes like the Hox gene clusters. Polycomb repressive complex 1 (PRC1), which contains histone H2A monoubiquitylating activity, is recruited to Hox genes to mediate their repression. Now, Chang et al., Lee et al., and the other new reports show that the enzymes UTX and JMJD3 are recruited to Hox promoters, remove H3K27me3, and reverse this repression… Thus, H3K27me3 is a crucial mark in deciding cell fate.
And thus, cells appear to have less and less room for free will.
- Rivenbark AG, Strahl BD. Unlocking cell fate.
Science, 19 October 2007, 318(5849): 403-404. DOI: 10.1126/science.1150321 - Chang B, Chen Y, Zhao Y, Bruick RK. JMJD6 Is a Histone Arginine Demethylase.
Science, 19 October 2007, 318(5849): 444-447. DOI: 10.1126/science.1145801 - Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Croce LD, Shiekhattar R. Demethylation of H3K27 Regulates Polycomb Recruitment and H2A Ubiquitination.
Science, 19 October 2007, 318(5849): 447-450. DOI: 10.1126/science.1149042
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Dan Rhoads
Dan is an American working in industry in a small Mediterranean country. He has a BSc in Molecular Biology and a PhD in Cancer Pharmacology and Biochemistry.
December 8th, 2007 at 6:27 pm
Hi
Thanks for the informative blog.
I need a clarification regarding numbering of Lys/Arg in histone methylation.As per my knowledge the N terminal of histones forms the histone tail and which are the site of epigentic modifications.But whenever we say position of an amino acid it is with respect to the c terminal end or considering initial methionine as No.1. What exactly is H3K4 methylation? Is this the 4th Lys residue from the c termius or the 4th Lys from the amino terminal end.Please clarify. Thanks and kindly reply to my mail at the earliest convenience.
December 9th, 2007 at 12:31 am
Good questions.
Amino acids are numbered from the first n-terminus, not the c-terminal end. As such, the K4 methylation site refers to the fourth amino acid beginning with the Methionine as you mention, which is a Lysine (K), of Histone H3.
And for the paper mentioned above, the same rule applies: H3K27 is the 27th amino acid from the n-terminus, and is also a lysine, which gets methylated.