Histone methylation, gene regulation, and heterochromatin

In Tetrahymena H3 methyl Lys-9 recruits chromodomain proteins, Pddlp and Pdd3p. Both of these proteins are involved in programmed DNA elimination that occurs during macronuclear development. H3 methylation at Lys-9 occurs only after the formation of the anlagen and at specific sites (internal eliminated sequences) [162]. 

The mammalian inactive X-chromosomes in females is associated with H3 methylated at Lys-9 but does not have H3 methylated at Lys-4 [165,166]. Deletion of murine Suv39h genes does not affect H3 Lys-9 methylation at the inactive X-chromosome. Thus, different histone methyltransferases are involved in the methylation of H3 Lys-9 in constitutive and facultative heterochromatin [166]. Further, HPl is not associated with the inactive X-chromosome. Methylation of H3 Lys-9 is an early event in X inactivation in mammals [167,168]. The H3 Lys-9 methylation occurs approximately at the same time as H3 Lys-9 hypoacetylation and Lys-4 hypomethylation, and happens before transcriptional inactivation of the X-linked genes. Upstream of the Xist gene, which codes for a strictly nuclear RNA involved in X inactivation, is a constitutive hotspot of H3 methylated at Lys-9. This early event of H3 Lys-9 methylation occurs simultaneously with or immediately following the association of Xist RNA with the X-chromosome. It has been proposed that the hotspot upstream of the Xist gene serves as a nucleation site for the spreading of Xist RNA and methylated Lys-9 H3 [167]. 

The inactive heterochromatic X-chromosome of C. elegans in males and hermaphrodites is devoid of H3 methyl Lys-4. Further the male single X-chromosome has H3 methyl Lys-9, which is not observed in the X-chromosomes of the hermaphrodite [169]. Male mouse XY bodies were also found to have high levels of H3 methyl Lys-9. 

In addition to heterochromatic silencing, SUV39H1 H3 methyltransferase and HPl are involved in repression of euchromatic genes. The transcription factor E2F has a pivotal role in regulating the expression of S-phase-specific genes. Repression of these genes is through the retinoblastoma (Rb) protein which binds to E2F. 

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