Periodic Reporting for period 4 - HISTONEMEMORY (New and Old Histones in Epigenetic Cell Memory)
Período documentado: 2021-11-01 hasta 2022-04-30
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 identified novel mechanisms in chromatin assembly and histone inheritance, and revealed that inheritance of histone modifications plays a critical role maintaining normal genome regulation and supporting embryonic differentiation.
We have uncovered a new histone chaperone DNAJC9 and identified its dual functionality as a molecular chaperone and histone chaperone that facilitates histone transactions in different cellular environments (Hammond et al., 2021, Mol Cell). This work demonstrates that heat shock molecular chaperones support histone supply chains from synthesis to deposition.
In a structure-function study of the NASP histone chaperone, we characterize two distinct histone binding modes and reveal the molecular basis for how NASP protects soluble histones from degradation (Bao, Carraro et al., Nucleic Acis Res 2022).