Abstract
The role of immortal DNA strands that co-segregate during mitosis of asymmetrically self-renewing distributed stem cells (DSCs) is unknown. Previously, investigation of immortal DNA strand function and molecular mechanisms responsible for their nonrandom co-segregation was precluded by difficulty in identifying DSCs and immortal DNA strands. Here, we report the use of two technological innovations, selective DSC expansion and establishment of H2A.Z chromosomal asymmetry as a specific marker of ‘immortal chromosomes,' to investigate molecular properties of immortal chromosomes and opposing ‘mortal chromosomes' in cultured mouse hair follicle DSCs. Although detection of the respective suppressive and activating H3K27me3 and H3K4me3 epigenetic marks on immortal chromosomes was similar to randomly segregated chromosomes, detection of both was lower on mortal chromosomes destined for lineage-committed sister cells. This global epigenomic feature of nonrandom co-segregation may reveal a mechanism that maintains an epigenome-wide ‘poised' transcription state, which preserves DSC identity, while simultaneously activating sister chromosomes for differentiation.
Highlights
We find that two well-described molecular marks of gene regulation, trimethylation of histone H3 lysines 27 and 4, display such an asymmetric distribution of detection between immortal chromosomes and mortal chromosomes in asymmetrically self-renewing mouse hair follicle-derived Distributed stem cells (DSCs)
The observed global co-asymmetry of increased H3K27me[3] and H3K4me[3] detection on immortal chromosomes is reminiscent of the gene-specific bivalency of these epigenetic marks that have been reported for embryonic cells,[27] embryonic stem cells,[8,9,27,28] and DSCs, including hematopoietic DSCs,[29] neural DSCs,[9] and primordial germ DSCs.[30]
This bivalent state is considered to hold in check transcription of genes involved in the developmental regulation and tissue-specific cell differentiation that are ‘poised’ in stem cells for initiation of developmental programs that occur with conversion to monovalent states
Summary
DSCs adopt a nonrandom form of mitotic chromosome segregation defined by continuous co-segregation of the set of chromosomes with the older template DNA strands to asymmetrically dividing DSCs.[7,10,11] These oldest DNA strands in asymmetrically self-renewing DSCs are called ‘immortal strands’,1 and the chromosomes bearing them are called ‘immortal chromosomes’.6 Immortal DNA strand cosegregation has been detected in an increasingly diverse range of tissues and vertebrate species.[7,12,13,14,15,16,17,18,19,20,21,22,23,24]. Cell strains with Xn-dependent growth were clonally derived Their DSCs properties include purinedependent asymmetric self-renewal, purine-dependent nonrandom sister chromatid segregation, long-term self-renewal, and production of multiple differentiated cell types of the skin and hair follicles.[7]. For much of their history, immortal DNA strands were mainly detected with retrospective assays based on their labeling properties with DNA base analogs.[7,12,13,14,15,17,18,19,20,21,22,23,24] With one recent exception,[21,24] these assays require chromosome. We find that two well-described molecular marks of gene regulation, trimethylation of histone H3 lysines 27 and 4, display such an asymmetric distribution of detection between immortal chromosomes and mortal chromosomes in asymmetrically self-renewing mouse hair follicle-derived DSCs
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