Old and newly synthesized histones are asymmetrically distributed in Drosophila intestinal stem cell divisions.

We report that preexisting (old) and newly synthesized (new) histones H3 and H4 are asymmetrically partitioned during the division of Drosophila intestinal stem cells (ISCs). Furthermore, the inheritance patterns of old and new H3 and H4 in postmitotic cell pairs correlate with distinct expression patterns of Delta, an important cell fate gene. To understand the biological significance of this phenomenon, we expressed a mutant H3T3A to compromise asymmetric histone inheritance. Under this condition, we observe an increase in Delta-symmetric cell pairs and overpopulated ISC-like, Delta-positive cells. Single-cell RNA-seq assays further indicate that H3T3A expression compromises ISC differentiation. Together, our results indicate that asymmetric histone inheritance potentially contributes to establishing distinct cell identities in a somatic stem cell lineage, consistent with previous findings in Drosophila male germline stem cells.

Characterization of histone inheritance patterns in the Drosophila female germline.

Stem cells have the unique ability to undergo asymmetric division which produces two daughter cells that are genetically identical, but commit to different cell fates. The loss of this balanced asymmetric outcome can lead to many diseases, including cancer and tissue dystrophy. Understanding this tightly regulated process is crucial in developing methods to treat these abnormalities. Here, we report that during a Drosophila female germline stem cell asymmetric division, the two daughter cells differentially inherit histones at key genes related to either maintaining the stem cell state or promoting differentiation, but not at constitutively active or silenced genes. We combine histone labeling with DNA Oligopaints to distinguish old versus new histones and visualize their inheritance patterns at a single-gene resolution in asymmetrically dividing cells in vivo. This strategy can be applied to other biological systems involving cell fate change during development or tissue homeostasis in multicellular organisms.

Asymmetric inheritance of epigenetic states in asymmetrically dividing stem cells.

Asymmetric cell division produces two cells that are genetically identical but each have distinctly different cell fates. During this process, epigenetic mechanisms play an important role in allowing the two daughter cells to have unique gene expression profiles that lead to their specific cell identities. Although the process of duplicating and segregating the genetic information during the cell cycle has been well studied, the question of how epigenetic information is duplicated and partitioned still remains. In this review, we discuss recent advances in understanding how epigenetic states are established and inherited, with emphasis on the asymmetric inheritance patterns of histones, DNA methylation, nonhistone proteins, RNAs, and organelles. We also discuss how misregulation of these processes may lead to diseases such as cancer and tissue degeneration.