Meiotic pairing and imprinted X chromatin assembly in Caenorhabditis elegans

Abstract

The genetic imprinting of individual loci or whole chromosomes, as in imprinted X-chromosome inactivation in mammals 1,2 , is established and reset during gametogenesis; defects in this process in the parent can result in disease in the offspring 3 . We describe a sperm-specific chromatin-based imprinting of the X chromosome in the nematode Caenorhabditis elegans that is restricted to histone H3 modifications. The epigenetic imprint is established during spermatogenesis and its stability in the offspring is affected by the presence of a pairing partner during meiosis in the parental germ line. We observed that DNA lacking a pairing partner during meiosis, the normal situation for the X chromosome in males, is targeted for methylation of histone H3 at Lys9 (H3-Lys9) and can be silenced. Targeting unpaired DNA for silencing during meiosis, a potential hallmark of genome defense, could therefore have a conserved role in imprinted X-chromosome inactivation and, ultimately, in sex chromosome evolution.The mechanisms by which imprinting is established during gametogenesis are not understood, but all such epigenetic phenomena clearly involve DNA methylation or histone modifications 4-7 . Methylation of H3-Lys9 is a highly conserved modification that is enriched in facultative and constitutive heterochromatin 8 . Methylation of histone H3 Lys4 (H3-Lys4), an opposing mark to methylation of H3-Lys9, is even more highly conserved and is enriched in transcriptionally competent or active DNA in all eukaryotes that have been examined 8 . Cytosine methylation, which is not found in all organisms, requires histone methylation in some species 9 , suggesting that histone modification may be the underlying mechanism guiding epigenetic processes. Indeed, methylation of histone H3 may provide an epigenetic mark during gametogenic imprinting of individual loci 10,11 . Histone modifications established during gametogenesis might therefore create a heritable epigenetic code that controls imprinted transcriptional competency in the offspring.The X chromosome in early adult germ cells of C. elegans lacks histone modifications associated with transcriptional competence 12 . The X chromosome is silenced in immature gametes of both sexes but shows sex-specific regulation during later gametic stages. In XX hermaphrodites, histones on the X chromosome become highly modified during early oogenesis, coincident with a burst of X-linked oocyte-specific gene expression 12 . In contrast, the unpaired X chromosome in (XO) males never accumulates 'activating' modifications during spermatogenesis but becomes enriched in methylated H3-Lys9 and condenses prematurely in pachytene nuclei 13 . This is markedly similar to what is observed for the XY body in mammalian spermatogenesis 13 . The X chromosome is also depleted of genes encoding sperm-enriched transcripts in C. elegans 12,14 . XX crossprogeny (produced from fertilization of a hermaphrodite by a male) therefore inherit sex chromosomes from each parent that differ substantially both in the spectrum ...

Marking Xs, together and separately

“…Bean et al 2 asked if these modifications might predict differences between the maternal and paternal X chromosome in XX zygotes produced by mating XO males with XX individuals. They assayed accumulation on chromosomes of histone modifications associated with transcriptional activation-dimethylation of histone H3 at Lys4 and acetylation of H3.…”

“…But this is not the complete story, because the X chromosome from an XO male germ line has a more stable imprint than the paternal X chromosome from hermaphroditic (XX) male germ cells. So Bean et al 2 asked if the meiotic pairing status of the X chromosome might influence the imprint, with an unpaired X chromosome acquiring a more stable imprint. They used the C. elegans sex determination system and sex-reversing mutants to show that pairing status of the X chromosome, more than germline sex, determines the chromatin imprint.…”

“…But the mark on the paternal X chromosome might not be indelible, because male mice who inherit their X chromosome from their fathers are not apparently developmentally impaired 15 . Notably, Bean et al 2 found that the imprint of the C. elegans paternal X chromosome disappears after several rounds of mitosis as it accumulates histone modifications. Although the observed histone mark disappeared, we don't yet know if the underlying imprint also disappeared.…”

“…Thus, it is not surprising that mitochondrial dysfunction contributes to diverse pathologies including neurodegeneration, diabetic complications and tumorigenesis. A recent study by Vamsi Mootha and colleagues 2 in Cell provides a basis for connecting mitochondrial pathologies with molecular etiology by identifying new mitochondrial proteins and profiling the extent of their tissue-specific diversity.…”

“…This epigenetic mark can result in differences in transcriptional activity, which is how many imprinting effects are discovered. On page 100 of this issue, Bean et al 2 provide a new twist to the imprinting story. They find that in Caenorhabditis elegans, an unpaired X chromosome acquires a chromatin imprint during gametogenic meiosis.…”