Symmetry from Asymmetry or Asymmetry from Symmetry?

Abstract

The processes of DNA replication and mitosis allow the genetic information of a cell to be copied and transferred reliably to its daughter cells. However, if DNA replication and cell division were always carried out in a symmetric manner, it would result in a cluster of tumor cells instead of a multicellular organism. Therefore, gaining a complete understanding of any complex living organism depends on learning how cells become different while faithfully maintaining the same genetic material. It is well recognized that the distinct epigenetic information contained in each cell type defines its unique gene expression program. Nevertheless, how epigenetic information contained in the parental cell is either maintained or changed in the daughter cells remains largely unknown. During the asymmetric cell division (ACD) of Drosophila male germline stem cells (GSCs), our previous work revealed that preexisting histones are selectively retained in the renewed stem cell daughter, whereas newly synthesized histones are enriched in the differentiating daughter cell. We also found that randomized inheritance of preexisting histones versus newly synthesized histones results in both stem cell loss and progenitor germ cell tumor phenotypes, suggesting that programmed histone inheritance is a key epigenetic player for cells to either remember or reset cell fates. Here we will discuss these findings in the context of current knowledge on DNA replication, polarized mitotic machinery, and ACD for both animal development and tissue homeostasis. We will also speculate on some potential mechanisms underlying asymmetric histone inheritance, which may be used in other biological events to achieve the asymmetric cell fates.

Stem cell mitotic drive ensures asymmetric epigenetic inheritance

“…Meanwhile, the previously identified asymmetric H3 (Tran et al, 2012), the differential phosphorylation at Thr3 of H3 (Xie et al, 2015), and the herein reported asymmetric sister centromeres act as a series of cis-factors. Together, temporally asymmetric microtubules coordinate with asymmetric sister centromeres to ensure differential sister chromatid attachment followed by segregation to generate two epigenetically distinct daughter cells, a phenomenon that is consistent with what has been previously hypothesized (Kahney et al, 2017;Malik, 2009;Yamashita, 2013). We propose that this series of interactions represent a 'mitotic drive' phenomenon during the asymmetric division of Drosophila male GSCs ( Figure 5I).…”

“…In general, ACD gives rise to two daughter cells with distinct fates, which could occur during development, as well as tissue homeostasis and regeneration (Clevers, 2005;Kahney et al, 2017;Knoblich, 2010;Morrison and Kimble, 2006;Venkei and Yamashita, 2018). Many studies have helped our understanding how this difference in cell fate could be achieved in stem cells.…”

“…Many types of adult stem cells undergo asymmetric cell division (ACD) to generate both a self-renewed stem cell and a daughter cell, which will subsequently differentiate (Clevers, 2005;Kahney et al, 2017;Knoblich, 2010;Morrison and Kimble, 2006;Venkei and Yamashita, 2018). Since stem cells have unique gene expression [e.g.…”

Unidirectional fork movement coupled with strand-specific histone incorporation ensures asymmetric histone inheritance

“…One important context for understanding cell fate specification is asymmetric cell division, where the two daughter cells establish different cell fates following a single division. Many stem cells undergo asymmetric division to produce both a self-renewing stem cell and a differentiating daughter cell [1][2][3][4][5] . Here we show that histone H4 is inherited asymmetrically in asymmetrically dividing Drosophila male germline stem cells, similar to H3 6 .…”

“…Asymmetric cell division (ACD) has been characterized in multiple systems where it plays an essential role in generating cells with distinct fates in development, homeostasis, and tissue regeneration 3,4,7,8 . Stem cells, in particular, often use ACD to give rise to one daughter cell capable of self-renewal and another daughter cell in preparation for terminal differentiation [1][2][3][4][5] . In spite of the crucial role that epigenetic mechanisms play in regulating cell fate decisions during development [9][10][11] , it remains unclear how stem cells and differentiating daughter cells establish different epigenomes following ACD.…”