During metazoan development, a single fertilized egg gives rise to various cell types, each with distinct appearances and functions. As the embryo develops, genetic information is reliably copied through DNA replication and subsequently transferred from one cell to its daughter cells through mitosis. Since the processes of DNA replication and mitosis always give rise to cells with identical genomes, it remains largely unknown how cells take on distinct cell fates in multicellular organisms. Cell fate is determined by selectively expressing a subset of the genome at the proper time, in the right place, and at the precise level. The unique gene expression program for each cell type is typically dictated by the epigenome; however, how the epigenetic information is transferred through mitosis in multicellular organisms remains unclear. Mis-regulation of cell fate specification underlies numerous diseases, such as various cancer and tissue degenerative diseases. Thus, understanding the mechanisms responsible for cell fate specification is not only important in enhancing our knowledge of basic biology, but also crucial for treating and preventing many diseases.

Previously, we made a novel discovery that preexisting old histones are selectively retained in the self-renewing stem cell, whereas newly synthesized histones are enriched in the differentiating daughter cell during asymmetric division of Drosophila male germline stem cells (Science, 2012, 338: 679). Mis-regulation of asymmetric histone inheritance leads to both stem cell loss and progenitor germ cell tumor phenotypes, suggesting that this process is critical to stem cell maintenance and progenitor cell differentiation (Cell, 2015, 163: 920). Since histone proteins are major carriers of epigenetic information in all eukaryotic organisms, our findings provide the first direct evidence that stem cell maintains its epigenetic information while the differentiating daughter cell undergoes epigenetic reprogramming. Notably, this asymmetry shows both cellular and molecular specificities. From a cellular perspective, asymmetric histone inheritance is specific to asymmetrically dividing stem cells, as symmetrically dividing progenitor germ cells show an overall symmetric histone inheritance pattern. From a molecular perspective, asymmetric histone inheritance is specific to canonical histones H3 and H4, but not H2A or H2B.

Since this significant finding in 2012, we have made several major discoveries that offer mechanistic insight to how asymmetric histones are established (Nature Struct. & Mol. Bio., 2019, 26: 732) and segregated (Cell Stem Cell, 2019, 25: 666) in Drosophila male germline stem cells. Recently, we discovered several unique features that differ between old and new histone-enriched sister chromatids, including nucleosome density, chromosomal condensation, and H3 Ser10 phosphorylation, leading to their differential association with Cdc6, an essential component of the pre-replication complex, and asynchronous initiation of DNA replication in the two resulting daughter cells [Developmental Cell, 2022, https://authors.elsevier.com/sd/article/S1534-5807(22)00247-7]. In addition, we systematically investigate histone inheritance patterns at a single-cell resolution in different systems. For example, we detected large genomic domains that distinctly display old versus new histones in both asymmetrically dividing Drosophila female germline stem cells (EMBO Reports, 2021, e51530) and Wnt3a-induced asymmetrically dividing mouse embryonic stem cells (Cell Reports, 2020, 32: 108003). We used two-color histone labeling with DNA Oligopaint FISH technology and found that the two daughter cells differentially inherit histones at key genes related to maintaining stem cell status or promoting differentiation, but not at genes that are constitutively active or silenced (EMBO Reports, 2021, e51530).

In summary, our previous discoveries have placed us at a unique position to solve the long-standing question in biology. We have already developed innovative strategies and plan to apply cutting-edge technologies to study how distinct epigenetic information is established and partitioned at any candidate DNA element in cell types of interest from multiple organisms. Our goal is to address a fundamental question: how do cells become different while faithfully maintaining the same genetic material? Addressing this question has far-reaching impact on our understanding of any complex living organism including human being.