Asymmetric Histone Inheritance: Establishment, Recognition, and Execution

Abstract

The discovery of biased histone inheritance in asymmetrically dividing Drosophila melanogaster male germline stem cells demonstrates one means to produce two distinct daughter cells with identical genetic material. This inspired further studies in different systems, which revealed that this phenomenon may be a widespread mechanism to introduce cellular diversity. While the extent of asymmetric histone inheritance could vary among systems, this phenomenon is proposed to occur in three steps: first, establishment of histone asymmetry between sister chromatids during DNA replication; second, recognition of sister chromatids carrying asymmetric histone information during mitosis; and third, execution of this asymmetry in the resulting daughter cells. By compiling the current knowledge from diverse eukaryotic systems, this review comprehensively details and compares known chromatin factors, mitotic machinery components, and cell cycle regulators that may contribute to each of these three steps. Also discussed are potential mechanisms that introduce and regulate variable histone inheritance modes and how these different modes may contribute to cell fate decisions in multicellular organisms.

Keywords: DNA replication–coupled histone assembly; epigenetic inheritance; epigenetic memory; mitotic drive; nonrandom chromatid segregation; nucleosome density.

Figure 1.. Modes of asymmetric histone inheritance:

(A) Global asymmetric histone inheritance presents as segregation of predominantly old or new histone-enriched sisters to daughter cells. (B) In contrast, local histone inheritance patterns are large-scale domains distinctly enriched for old or new histones.

Figure 2.. Replication-coupled chromatin assembly and restoration:

Histone chaperones and replisome components orchestrate disassembly of parental chromatin ahead of the replication fork. Concurrently, parental histones are shuttled behind the fork while new histones are recruited to stimulate chromatin restoration on newly synthesized DNA.

Figure 3.. Centromere structure:

(A) Schematic of centromere, kinetochore, and microtubule in somatic cells. (B) The canonical function of the centromere during symmetric cell division (SCD).

Figure 4.. Meiotic drive in mice:

Mechanisms of centromere drive. (A) Stronger centromeres have more minor satellite repeats and build larger kinetochores that recruit more destabilizers than weaker centromeres. (B) The cortical positioning of the spindle induces microtubule tyrosination, leading to directional flipping until the stronger centromeres are preferentially oriented towards the egg side.

Figure 5.. Asymmetric histone inheritance (global vs local):

(A) Representation of the global asymmetric inheritance of histone H3 and H4 in D. melanogaster male GSC and ISC. (B) Representation of the local asymmetric inheritance of histone H3 and H4 in D. melanogaster female GSC and induced mouse ESCs.

Figure 6.. Mitotic drive in D. melanogaster GSCs:

Mechanisms of the mitotic drive. (A) Stronger centromeres build larger kinetochores that bind more microtubules compared with weaker centromeres. (B) Sister chromatids with asymmetric histone epigenome in male GSCs. A temporal asymmetry of microtubules activity, NEBD, and CENP-A epigenetic asymmetry tightly coordinate to ensure non-random segregation.