Thursday, April 3, 2008

Dynamic "cold" genetic material

Two recent papers changed the concept of "cold" DNA, the so called heterochromatin.

1. Proliferation-dependent and cell cycle–regulated transcription of mouse pericentric heterochromatin
The Journal of Cell Biology, 2007; Vol. 179, No. 3, 411-421

Cell cycle control of centromeric repeat transcription and heterochromatin assembly

Genetic information resides in DNA in most organisms. DNA is packed into chromatin and stays in nucleus of a cell. There are two different package status: one loose and one tight. These are the original concepts of euchromatin and heterochromatin coined by German botanist Heitz 80 years ago. He proposed that heterochromatin reflects a functionally inactive state of the genome (all DNA information of an organism). Decades of research have generally been supportive to this idea. Heterochromatin is generally gene poor, highly packed, late replicating, and has a very low recombination rate. Modern molecular hallmarks of heterochromatin generally include heterochromatin protein 1 (HP1, swi6 in fission yeast) and methylation of histone H3 lysine 9 (H3K9) by histone methyltransferase (HMTase) (suv39, clr4). On the whole, Heitz’s original “inactive state” hypothesis still holds until recently.

The first paper demonstrated cell-cycle-specific transient disruption and transcription of mouse pericentric heterochromatin. It shows that mammalian pericentric heterochromatin is transcribed by RNA polymerase II twice during the cell cycle. A heterogeneous population of short RNAs (about 150 bp) is generated during mitosis, while a longer (mostly >1 kb) population is produced in late G1 and early S phase. Cell cycle regulation of pericentric transcription does not require Suv39h1,2-dependent chromatin modification, but it does require passage through "Start" in G1 phase. Future studies will determine whether these mammalian pericentric transcripts are important for heterochromatin formation as they are in fission yeast, as reported in the second paper.
in this paper, at regions serving as RNAi-dependent heterochromatin nucleation centers in fission yeast (in the pericentric, mating-type, and telomere regions), heterochromatin is abundant during G2 but greatly reduced during M, G1 and S phases. Heterochromatin reduction in M, G1 and S is correlated with phosphorylation of histone H3 on serine 10 (H3S10) and with binding of condensins. Genetic analyses show that condensin binding (in M and G1) and methylations of H3K36 (in S) and H3K9 (in G2) all contribute toward proper heterochromatin formation in G2 and toward proper regulation of transcription of the RNAi-dependent nucleation centers during S phase.

Because centromere /heterochromatin defect is almost the most common feature of cancers, this transcription could be the most basic factor during cancer formation. It might be that this transcription leads centromere structure problem, which leads to chromosome segregation defect which cause gene mutation etc. and cancer eventually.

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