Skip to main content

New and Old Histones in Epigenetic Cell Memory

Periodic Reporting for period 2 - HISTONEMEMORY (New and Old Histones in Epigenetic Cell Memory)

Reporting period: 2018-11-01 to 2020-04-30

Cell type specific organization of DNA into chromatin is an important determinant of gene expression and cell identity. During cell division, epigenetic information in chromatin must be transmitted to daughter cells in order to maintain cell identity or commit to a developmental program. However, it remains unknown how epigenetic states are inherited during cell division. Elucidating molecular mechanisms underlying epigenetic cell memory thus represents a major challenge in biology critical to understand development and disease.

Chromatin undergoes genome-wide disruption during DNA replication and histone marks are diluted 2-fold due to new histone deposition. Yet, how this impacts on establishment and maintenance of gene expression programs is not known. We hypothesize that chromatin replication represents a critical window for epigenetic cell memory and cell fate decisions, and predict that three histone-based processes play critical roles in guarding cell identity: 1) new histone deposition to regulate nucleosome occupancy and transcription factor (TF) binding, 2) accurate transmission of old modified histones by dedicated recycling machinery, and 3) recruitment of regulatory proteins to new and old histones to direct epigenome maintenance. To dissect these events mechanistically and test causal roles in cell fate decisions, we have set up a research program integrating explorative proteomics and histone chaperone structure-function analysis with stem cell biology and new cutting-edge genomic tools developed by my research group.
We have discovered that MCM2, part of the replicative helicase, is responsible for segregation of parental histones to lagging strand and ensuring balanced transmission of histone post-translational modifications (PTMs) to both DNA strands (Petryk et al., 2018, Science). Mouse ES cells expressing MCM2 histone binding mutants are now providing a powerful and unique tool to study the importance of old histone recycling for gene regulation and cell fate decisions.
The proposed research will provide a major advance in understanding epigenetic cell memory by 1) identifying novel mechanisms of histone chaperoning and deposition specific to new and old histones, and 2) addressing how the inheritance of histone modifications during DNA replication impact gene regulation and cell fate decisions.